bims-kracam 2021-09-19 papers

on K-Ras in cancer metabolism

Issue of 2021‒09‒19
thirty-four papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development

Pharmacologic approaches to amino acid depletion for cancer therapy.
Targeting mutated GTPase KRAS in tumor therapies.
Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy.
Cashing in on ferroptosis against tumor cells: Usher in the next chapter.
The possible role of methylglyoxal metabolism in cancer.
Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer.
Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling.
USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer.
Mito-Bomb: Targeting Mitochondria for Cancer Therapy.
Natural Small Molecules Targeting NF-κB Signaling in Glioblastoma.
Therapeutic Targeting of Autophagy in Pancreatic Cancer.
Cancer and diabetes: the interlinking metabolic pathways and repurposing actions of antidiabetic drugs.
Glioma Stem-Like Cells and Metabolism: Potential for Novel Therapeutic Strategies.
Modulation of inflammation by phytochemicals to enhance efficacy and reduce toxicity of cancer chemotherapy.
Monoethanolamine-induced glucose deprivation promotes apoptosis through metabolic rewiring in prostate cancer.
Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites.
Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia.
Epigenetic alterations and mechanisms that drive resistance to targeted cancer therapies.
Metabolic homeostasis: it's all in the timing.
Nucleotide Metabolism Behind Epigenetics.
Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment.
Hyperglycemic conditions proliferate triple negative breast cancer cells: role of ornithine decarboxylase.
Biological and pharmacological activities of noscapine: Focusing on its receptors and mechanisms.
Crosslink between p53 and metastasis: focus on epithelial-mesenchymal transition, cancer stem cell, angiogenesis, autophagy, and anoikis.
Celastrol in cancer therapy: Recent developments, challenges and prospects.
Characterization of KRAS Mutation Subtypes in Non-Small Cell Lung Cancer.
Oxidative phosphorylation is a metabolic vulnerability in chemotherapy-resistant triple negative breast cancer.
Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer.
The roles of epigenetics in cancer progression and metastasis.
The glycine betaine role in neurodegenerative, cardiovascular, hepatic, and renal diseases: Insights into disease and dysfunction networks.
Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells.
Brief report: The uricase mutation in humans increases our risk for cancer growth.
Molecular and Metabolomic Investigation of Celecoxib Antiproliferative Activity in Mono-and Combination Therapy Against Breast Cancer Cell Models.
Elemene Nanoemulsion Inhibits Metastasis of Breast Cancer by ROS Scavenging.

Mol Carcinog. 2021 Sep 17.

Pharmacologic approaches to amino acid depletion for cancer therapy.

Carly S Wilder, Zhao Chen, John DiGiovanni.

  Cancer cells undergo metabolic reprogramming to support increased demands in bioenergetics and biosynthesis and to maintain reactive oxygen species at optimum levels. As metabolic alterations are broadly observed across many cancer types, metabolic reprogramming is considered a hallmark of cancer. A metabolic alteration commonly seen in cancer cells is an increased demand for certain amino acids. Amino acids are involved in a wide range of cellular functions, including proliferation, redox balance, bioenergetic and biosynthesis support, and homeostatic functions. Thus, targeting amino acid dependency in cancer is an attractive strategy for a number of cancers. In particular, pharmacologically mediated amino acid depletion has been evaluated as a cancer treatment option for several cancers. Amino acids that have been investigated for the feasibility of drug-induced depletion in preclinical and clinical studies for cancer treatment include arginine, asparagine, cysteine, glutamine, lysine, and methionine. In this review, we will summarize the status of current research on pharmacologically mediated amino acid depletion as a strategy for cancer treatment and potential chemotherapeutic combinations that synergize with amino acid depletion to further inhibit tumor growth and progression.

Keywords:  amino acid depletion; amino acid metabolism; cancer; cancer therapy; metabolic reprogramming

DOI:  https://doi.org/10.1002/mc.23349
Eur J Med Chem. 2021 Sep 04. pii: S0223-5234(21)00665-6. [Epub ahead of print]226 113816

Targeting mutated GTPase KRAS in tumor therapies.

Guangjin Fan, Linlin Lou, Zhendong Song, Xiaolei Zhang, Xiao-Feng Xiong.

  Kirsten rat sarcoma virus oncogene (KRAS) mutation accounts for approximately 85% of RAS-driven cancers, and participates in multiple signaling pathways and mediates cell proliferation, differentiation and metabolism. KRAS has been considered as an "undruggable" target due to the lack of effective direct inhibitors, although high frequency of KRAS mutations have been identified in multiple carcinomas in the past decades. Encouragingly, the KRASG12C inhibitor AMG510 (sotorasib), which has been approved for treating NSCLC and CRC recently, makes directly targeting KRAS the most promising strategy for cancer therapy. To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed.

Keywords:  Covalent inhibitors; GTPase; KRAS; Tumor therapies

DOI:  https://doi.org/10.1016/j.ejmech.2021.113816
Front Pharmacol. 2021 ;12 748149

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy.

Qiang Xie, Yi Chen, Huidan Tan, Bo Liu, Ling-Li Zheng, Yandong Mu.

  Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.

Keywords:  autophagy; cancer therapy; natural compound; pathway; small-molecule drug

DOI:  https://doi.org/10.3389/fphar.2021.748149
Life Sci. 2021 Sep 14. pii: S0024-3205(21)00945-0. [Epub ahead of print] 119958

Cashing in on ferroptosis against tumor cells: Usher in the next chapter.

Mehdi Rabiee Valashedi, Nima Najafi-Ghalehlou, Amirsadegh Nikoo, Chia Bamshad, Kazuo Tomita, Yoshikazu Kuwahara, Tomoaki Sato, Amaneh Mohammadi Roushandeh, Mehryar Habibi Roudkenar.

  Ferroptosis is a new type of non-apoptotic regulated cell death (RCD) driven by unrestricted lethal lipid peroxidation, which is totally distinct from other forms of RCD in genetic and biochemical characteristics. It is generally believed that iron dependency, malfunction of the redox system, and excessive lipid peroxidation are the main hallmarks of ferroptosis. Accumulating pieces of evidence over the past few years have shown that ferroptosis is tightly related to various types of diseases, especially cancers. Ferroptosis has recently attracted great attention in the field of cancer research. A plethora of evidence shows that employing ferroptosis as a powerful weapon can remarkably enhance the efficacy of tumor cell annihilation. Better knowledge of the ferroptosis mechanisms and their interplay with cancer biology would enable us to use this fashionable tool in the best way. Herein, we will briefly present the relevant mechanisms of ferroptosis, the multifaceted relation between ferroptosis and cancer, encompassing tumor immunity, overcoming chemoresistance, and epithelial to mesenchymal transition. In the end, we will also briefly discuss the potential approaches to ferroptosis-based cancer therapy, such as using drugs and small molecules, nanoparticles, mitochondrial targeting, and photodynamic therapy.

Keywords:  Cancer therapy; Chemoresistance; Ferroptosis; Oxidative stress; Tumor immunity

DOI:  https://doi.org/10.1016/j.lfs.2021.119958
J Enzyme Inhib Med Chem. 2021 Dec;36(1): 2010-2015

The possible role of methylglyoxal metabolism in cancer.

Khalid O Alfarouk, Saad S Alqahtani, Saeed Alshahrani, Jakob Morgenstern, Claudiu T Supuran, Stephan J Reshkin.

  Tumours reprogram their metabolism to acquire an evolutionary advantage over normal cells. However, not all such metabolic pathways support energy production. An example of these metabolic pathways is the Methylglyoxal (MG) one. This pathway helps maintain the redox state, and it might act as a phosphate sensor that monitors the intracellular phosphate levels. In this work, we discuss the biochemical step of the MG pathway and interrelate it with cancer.

Keywords:  Methylglyoxal; cancer; enzyme; pH; redox

DOI:  https://doi.org/10.1080/14756366.2021.1972994
Cancer Lett. 2021 Sep 08. pii: S0304-3835(21)00454-7. [Epub ahead of print]

Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer.

Rumi Itoyama, Noriko Yasuda-Yoshihara, Fumimasa Kitamura, Tadahito Yasuda, Luke Bu, Atsuko Yonemura, Tomoyuki Uchihara, Kota Arima, Xichen Hu, Zhang Jun, Yuya Okamoto, Takahiko Akiyama, Kohei Yamashita, Yosuke Nakao, Toshihiko Yusa, Yuki Kitano, Takaaki Higashi, Tatsunori Miyata, Katsunori Imai, Hiromitsu Hayashi, Yo-Ichi Yamashita, Takumi Mikawa, Hiroshi Kondoh, Hideo Baba, Takatsugu Ishimoto.

  Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.

Keywords:  Cancer metabolism; Glycolysis; Nutrient microenvironment; Pancreatic cancer; Serine biosynthesis

DOI:  https://doi.org/10.1016/j.canlet.2021.09.007
Front Mol Neurosci. 2021 ;14 732120

Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling.

Darío García-Rodríguez, Alfredo Giménez-Cassina.

  Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called "ketogenic diets," which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.

Keywords:  acetoacetate; brain metabolism; epilepsy; ketogenic diet; ketone bodies; metabolic signaling; neuronal excitability; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fnmol.2021.732120
Genes Dev. 2021 Sep 16.

USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer.

Pingping Hou, Xingdi Ma, Zecheng Yang, Qiang Zhang, Chang-Jiun Wu, Jun Li, Lin Tan, Wantong Yao, Liang Yan, Xin Zhou, Alec C Kimmelman, Philip L Lorenzi, Jianhua Zhang, Shan Jiang, Denise Spring, Y Alan Wang, Ronald A DePinho.

  Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

Keywords:  KRAS; MARK3; USP21; macropinocytosis; targeted therapy resistance

DOI:  https://doi.org/10.1101/gad.348787.121
Adv Mater. 2021 Sep 12. e2007778

Mito-Bomb: Targeting Mitochondria for Cancer Therapy.

Xiaolu Guo, Naidi Yang, Wenhui Ji, Hang Zhang, Xiao Dong, Zhiqiang Zhou, Lin Li, Han-Ming Shen, Shao Q Yao, Wei Huang.

  Cancer has been one of the most common life-threatening diseases for a long time. Traditional cancer therapies such as surgery, chemotherapy (CT), and radiotherapy (RT) have limited effects due to drug resistance, unsatisfactory treatment efficiency, and side effects. In recent years, photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) have been utilized for cancer treatment owing to their high selectivity, minor resistance, and minimal toxicity. Accumulating evidence has demonstrated that selective delivery of drugs to specific subcellular organelles can significantly enhance the efficiency of cancer therapy. Mitochondria-targeting therapeutic strategies are promising for cancer therapy, which is attributed to the essential role of mitochondria in the regulation of cancer cell apoptosis, metabolism, and more vulnerable to hyperthermia and oxidative damage. Herein, the rational design, functionalization, and applications of diverse mitochondria-targeting units, involving organic phosphine/sulfur salts, quaternary ammonium (QA) salts, peptides, transition-metal complexes, guanidinium or bisguanidinium, as well as mitochondria-targeting cancer therapies including PDT, PTT, CDT, and others are summarized. This review aims to furnish researchers with deep insights and hints in the design and applications of novel mitochondria-targeting agents for cancer therapy.

Keywords:  cancer therapy; chemodynamic therapy; mitochondria; photodynamic therapy; photothermal therapy

DOI:  https://doi.org/10.1002/adma.202007778
Front Pharmacol. 2021 ;12 703761

Natural Small Molecules Targeting NF-κB Signaling in Glioblastoma.

Md Sahab Uddin, Md Tanvir Kabir, Abdullah Al Mamun, Md Shahid Sarwar, Fatema Nasrin, Talha Bin Emran, Ibtesam S Alanazi, Abdur Rauf, Ghadeer M Albadrani, Amany A Sayed, Shaker A Mousa, Mohamed M Abdel-Daim.

  Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes that mediate various cellular activities, including propagation, differentiation, motility, and survival. Abnormal activation of NF-κB is a common incidence in several cancers. Glioblastoma multiforme (GBM) is the most aggressive brain cancer described by high cellular heterogeneity and almost unavoidable relapse following surgery and resistance to traditional therapy. In GBM, NF-κB is abnormally activated by various stimuli. Its function has been associated with different processes, including regulation of cancer cells with stem-like phenotypes, invasion of cancer cells, and radiotherapy resistance identification of mesenchymal cells. Even though multimodal therapeutic approaches such as surgery, radiation therapy, and chemotherapeutic drugs are used for treating GBM, however; the estimated mortality rate for GBM patients is around 1 year. Therefore, it is necessary to find out new therapeutic approaches for treating GBM. Many studies are focusing on therapeutics having less adverse effects owing to the failure of conventional chemotherapy and targeted agents. Several studies of compounds suggested the involvement of NF-κB signaling pathways in the growth and development of a tumor and GBM cell apoptosis. In this review, we highlight the involvement of NF-κB signaling in the molecular understanding of GBM and natural compounds targeting NF-κB signaling.

Keywords:  NF-κB; brain cancer; glioblastoma; malignant; natural products; small molecules

DOI:  https://doi.org/10.3389/fphar.2021.703761
Surg Oncol Clin N Am. 2021 Oct;pii: S1055-3207(21)00041-7. [Epub ahead of print]30(4): 709-718

Therapeutic Targeting of Autophagy in Pancreatic Cancer.

Mona Foth, Ignacio Garrido-Laguna, Conan G Kinsey.

  This article provides a brief review of the therapeutic opportunity of inhibiting autophagy in pancreatic cancer. The autophagic process, importance of autophagy in pancreatic cancer, relevant clinical trials, and new agents in preclinical and clinical development are discussed.

Keywords:  Autophagy; Autophagy clinical trials; Pancreatic cancer; Pancreatic cancer clinical trials; Therapeutics

DOI:  https://doi.org/10.1016/j.soc.2021.06.001
Cancer Cell Int. 2021 Sep 17. 21(1): 499

Cancer and diabetes: the interlinking metabolic pathways and repurposing actions of antidiabetic drugs.

Ahmed Olatunde, Manisha Nigam, Rahul Kunwar Singh, Abhaya Shikhar Panwar, Abdulwahab Lasisi, Fahad A Alhumaydhi, Vijay Jyoti Kumar, Abhay Prakash Mishra, Javad Sharifi-Rad.

  Cancers are regarded as one of the main causes of death and result in high health burden worldwide. The management of cancer include chemotherapy, surgery and radiotherapy. The chemotherapy, which involves the use of chemical agents with cytotoxic actions is utilised as a single treatment or combined treatment. However, these managements of cancer such as chemotherapy poses some setbacks such as cytotoxicity on normal cells and the problem of anticancer drug resistance. Therefore, the use of other therapeutic agents such as antidiabetic drugs is one of the alternative interventions used in addressing some of the limitations in the use of anticancer agents. Antidiabetic drugs such as sulfonylureas, biguanides and thiazolidinediones showed beneficial and repurposing actions in the management of cancer, thus, the activities of these drugs against cancer is attributed to some of the metabolic links between the two disorders and these includes hyperglycaemia, hyperinsulinemia, inflammation, and oxidative stress as well as obesity. Furthermore, some studies showed that the use of antidiabetic drugs could serve as risk factors for the development of cancerous cells particularly pancreatic cancer. However, the beneficial role of these chemical agents overweighs their detrimental actions in cancer management. Hence, the present review indicates the metabolic links between cancer and diabetes and the mechanistic actions of antidiabetic drugs in the management of cancers.

Keywords:  Anticancer drugs; Antidiabetic drugs; Cancer; Diabetes; Repurposing action

DOI:  https://doi.org/10.1186/s12935-021-02202-5
Front Oncol. 2021 ;11 743814

Glioma Stem-Like Cells and Metabolism: Potential for Novel Therapeutic Strategies.

Abigail Harland, Xia Liu, Mattia Ghirardello, M Carmen Galan, Claire M Perks, Kathreena M Kurian.

  Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance.

Keywords:  cancer metabolism; cancer stem cell (CSC); glioma stem-like cell; metabolic reprogramming; therapeutic strategies

DOI:  https://doi.org/10.3389/fonc.2021.743814
Crit Rev Food Sci Nutr. 2021 Sep 16. 1-15

Modulation of inflammation by phytochemicals to enhance efficacy and reduce toxicity of cancer chemotherapy.

Taha Koray Sahin, Birdal Bilir, Omer Kucuk.

  Treatment of cancer with chemotherapeutic drugs is associated with numerous adverse effects as well as the eventual development of resistance to chemotherapy. There is a great need for complementary therapies such as botanicals and nutritional supplements with little or no side effects that prevent resistance to chemotherapy and reduce its adverse effects. Inflammation plays a major role in the development of chemoresistance and the adverse effects of chemotherapy. Phytochemicals have well-established anti-inflammatory effects; thus, they could be used as complementary therapies along with chemotherapy to increase its efficacy and reduce its toxicity. Botanical compounds inhibit the NF-κB signaling pathway, which plays an important role in the generation of inflammation, chemotherapy resistance, and modulation of cell survival and apoptosis. Botanicals have previously been studied extensively for their cancer chemopreventive activities and are generally considered safe for human consumption. The present review focuses on the modulation of inflammation by phytochemicals and their role in increasing the efficacy and reducing the toxicity of cancer chemotherapy.

Keywords:  Phytochemicals; cancer; chemotherapy; inflammation; sensitization; toxicity

DOI:  https://doi.org/10.1080/10408398.2021.1976721
Theranostics. 2021 ;11(18): 9089-9106

Monoethanolamine-induced glucose deprivation promotes apoptosis through metabolic rewiring in prostate cancer.

Chakravarthy Garlapati, Shriya Joshi, Ravi Chakra Turaga, Manjari Mishra, Michelle D Reid, Shobhna Kapoor, Liana Artinian, Vincent Rehder, Ritu Aneja.

  Rationale: Cancer cells rely on glucose metabolism for fulfilling their high energy demands. We previously reported that monoethanolamine (Etn), an orally deliverable lipid formulation, reduced intracellular glucose and glutamine levels in prostate cancer (PCa). Glucose deprivation upon Etn treatment exacerbated metabolic stress in PCa, thereby enhancing cell death. Moreover, Etn was potent in inhibiting tumor growth in a PCa xenograft model. However, the precise mechanisms underlying Etn-induced metabolic stress in PCa remain elusive. The purpose of the present study was to elucidate the mechanisms contributing to Etn-mediated metabolic rewiring in PCa. Methods: Glucose transporters (GLUTs) facilitate glucose transport across the plasma membrane. Thus, we assessed the expression of GLUTs and the internalization of GLUT1 in PCa. We also evaluated the effects of Etn on membrane dynamics, mitochondrial structure and function, lipid droplet density, autophagy, and apoptosis in PCa cells. Results: Compared to other GLUTs, GLUT1 was highly upregulated in PCa. We observed enhanced GLUT1 internalization, altered membrane dynamics, and perturbed mitochondrial structure and function upon Etn treatment. Etn-induced bioenergetic stress enhanced lipolysis, decreased lipid droplet density, promoted accumulation of autophagosomes, and increased apoptosis. Conclusion: We provide the first evidence that Etn alters GLUT1 trafficking leading to metabolic stress in PCa. By upregulating phosphatidylethanolamine (PE), Etn modulates membrane fluidity and affects mitochondrial structure and function. Etn also induces autophagy in PCa cells, thereby promoting apoptosis. These data strongly suggest that Etn rewires cellular bioenergetics and could serve as a promising anticancer agent for PCa.

Keywords:  apoptosis; autophagy; metabolism; monoethanolamine; prostate cancer

DOI:  https://doi.org/10.7150/thno.62724
Cell Chem Biol. 2021 Sep 11. pii: S2451-9456(21)00403-7. [Epub ahead of print]

Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites.

Joyce H Lee, Eric P Mosher, Young-Sam Lee, Namandjé N Bumpus, James M Berger.

  Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.

Keywords:  DNA topology; ICRF-187; TCA cycle; cancer; chemotherapy; dexrazoxane; etoposide; metabolism; topoisomerase

DOI:  https://doi.org/10.1016/j.chembiol.2021.08.014
Cancer Sci. 2021 Sep 17.

Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia.

Yusuke Saito, Mariko Kinoshita, Ai Yamada, Sayaka Kawano, Hong-Shan Liu, Sachiyo Kamimura, Midori Nakagawa, Syun Nagasawa, Tadao Taguchi, Shuhei Yamada, Hiroshi Moritake.

Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway (PPP). Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and TCA cycle, thus suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene-independent leukemia.

DOI: https://doi.org/10.1111/cas.15138
Cancer Res. 2021 Sep 16. pii: canres.1606.2021. [Epub ahead of print]

Epigenetic alterations and mechanisms that drive resistance to targeted cancer therapies.

Narendra Wajapeyee, Romi Gupta.

Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some cancer patients experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell non-autonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1606
Endocrinology. 2021 Sep 17. pii: bqab199. [Epub ahead of print]

Metabolic homeostasis: it's all in the timing.

Patricia L Brubaker, Alexandre Martchenko.

  Cross-talk between peripheral tissues is essential to ensure the coordination of nutrient intake with disposition during the feeding period, thereby preventing metabolic disease. This Mini-review considers the interactions between the key peripheral tissues that constitute the metabolic clock, each of which is considered in a separate Mini-review in this collation of articles published in Endocrinology in 2020/2021, by: Martchenko et al. (Circadian Rhythms and the Gastrointestinal Tract: Relationship to Metabolism and Gut Hormones); Alvarez et al. (The Microbiome as a Circadian Coordinator of Metabolism); Seshadri et al. (Circadian Regulation of the Pancreatic Beta Cell); McCommis et al. (The Importance of Keeping Time in the Liver); Oosterman et al. (The Circadian Clock, Shift Work, and Tissue-Specific Insulin Resistance); and Heyde et al. (Contributions of White and Brown Adipose Tissues to the Circadian Regulation of Energy Metabolism). The use of positive- and negative-feedback signals, both hormonal and metabolic, between these tissues ensures that peripheral metabolic pathways are synchronized with the timing of food intake, thus optimizing nutrient disposition and preventing metabolic disease. Collectively, these articles highlight the critical role played by the circadian clock in the maintenance of metabolic homeostasis.

Keywords:  adipocyte; circadian; hepatocyte; intestine; islet; metabolism; microbiome; myocyte

DOI:  https://doi.org/10.1210/endocr/bqab199
Front Endocrinol (Lausanne). 2021 ;12 731648

Nucleotide Metabolism Behind Epigenetics.

Tamaki Suganuma, Jerry L Workman.

  The mechanisms of epigenetic gene regulation-histone modifications, chromatin remodeling, DNA methylation, and noncoding RNA-use metabolites as enzymatic cofactors and substrates in reactions that allow chromatin formation, nucleotide biogenesis, transcription, RNA processing, and translation. Gene expression responds to demands from cellular processes that use specific metabolites and alters or maintains cellular metabolic status. However, the roles of metabolites-particularly nucleotides-as regulatory molecules in epigenetic regulation and biological processes remain largely unknown. Here we review the crosstalk between gene expression, nucleotide metabolism, and cellular processes, and explore the role of metabolism in epigenetics as a critical regulator of biological events.

Keywords:  ADP-ribosylation; DNA damage; NAD; RNA editing; chromatin modifiers; histone modifications; metabolism; nucleotide metabolism

DOI:  https://doi.org/10.3389/fendo.2021.731648
Drug Des Devel Ther. 2021 ;15 3749-3764

Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment.

Kunpeng Wang, Xiongying Miao, Fanhua Kong, Siqi Huang, Jinggang Mo, Chong Jin, Yanwen Zheng.

  Background and Aim: Pancreatic cancer is one of the most malignant tumors worldwide. Zuojin pills (ZJP), a traditional Chinese medicine (TCM) formula, which can treat a variety of cancers. However, the active compounds present in ZJP and the potential mechanisms through which ZJP acts against pancreatic cancer have not been thoroughly investigated.Methods: Data on pancreatic cancer-related genes, bioactive compounds, and potential targets of ZJP were downloaded from public databases. Bioinformatics analysis, including protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, was conducted to identify important components, potential targets, and signaling pathways through which ZJP affects pancreatic cancer. The results of this analysis were verified by in vitro experiments.
Results: The network pharmacology analysis results showed that 41 compounds and 130 putative target genes of ZJP were associated with anti-pancreatic cancer effects. ZJP may exert its inhibitory effects against pancreatic cancer by acting on key targets such as JUN, TP53, and MAPK1. Moreover, KEGG analysis indicated that the anti-pancreatic cancer effect of ZJP was mediated by multiple pathways, such as the PI3K-AKT, IL-17, TNF, HIF-1, and P53 signaling pathways. Among these, the PI3K-AKT signaling pathway, which included the highest number of enriched genes, may play a more important role in treating pancreatic cancer. The in vitro results showed that ZJP significantly inhibits the cell cycle and cell proliferation through the PI3K/AKT/caspase pathway and that it can induce apoptosis of pancreatic cancer cells, consistent with the results predicted by network pharmacological methods.
Conclusion: This study preliminarily investigated the pharmacological effects of ZJP, which appear to be mediated by multiple compounds, targets and pathways, and its potential therapeutic effect on pancreatic cancer. Importantly, our work provides a promising approach for the identification of compounds in TCM and the characterization of therapeutic mechanisms.

Keywords:  Zuojin pill; apoptosis; network pharmacology; pancreatic cancer; proliferation; traditional Chinese medicine

DOI:  https://doi.org/10.2147/DDDT.S323360
Breast Cancer Res Treat. 2021 Sep 16.

Hyperglycemic conditions proliferate triple negative breast cancer cells: role of ornithine decarboxylase.

Caleb C Capellen, Jose Ortega-Rodas, M Jane Morwitzer, Hadassha M N Tofilau, Matthew Dunworth, Robert A Casero, Surabhi Chandra.

  PURPOSE: Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose (HG) conditions.METHODS: Studies were performed with varying concentrations of glucose (5-25 mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A.
RESULTS: There was a significant increase in proliferation with HG (25 mM) at 48-72 h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5 mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells.
CONCLUSIONS: Our cellular findings indicate that polyamine inhibition should be explored in patient population as a target for future chemotherapeutics in diabetic breast cancer.

Keywords:  Breast cancer; Diabetes; High glucose; Ornithine decarboxylase; Polyamine; Putrescine

DOI:  https://doi.org/10.1007/s10549-021-06388-0
Biofactors. 2021 Sep 17.

Biological and pharmacological activities of noscapine: Focusing on its receptors and mechanisms.

Fahimeh Nourbakhsh, Vahid Reza Askari.

  Noscapine has been mentioned as one of the effective drugs with potential therapeutic applications. With few side effects and amazing capabilities, noscapine can be considered different from other opioids-like structure compounds. Since 1930, extensive studies have been conducted in the field of pharmacological treatments from against malaria to control cough and cancer treatment. Furthermore, recent studies have shown that noscapine and some analogues, like 9-bromonoscapine, amino noscapine, and 9-nitronoscapine, can be used to treat polycystic ovaries syndrome, stroke, and other diseases. Given the numerous results presented in this field and the role of different receptors in the therapeutic effects of noscapine, we aimed to review the properties, therapeutic effects, and the role of receptors in the treatment of noscapine.

Keywords:  bradykinins; cancer; microtubule targeting drugs; noscapine; receptors; therapeutics

DOI:  https://doi.org/10.1002/biof.1781
Mol Biol Rep. 2021 Sep 14.

Crosslink between p53 and metastasis: focus on epithelial-mesenchymal transition, cancer stem cell, angiogenesis, autophagy, and anoikis.

Ghader Babaei, Azadeh Aliarab, Mehdi Asghari Vostakolaei, Masumeh Hotelchi, Roghaiyeh Neisari, Shiva Gholizadeh-Ghaleh Aziz, Masumeh Rajabi Bazl.

  INTRODUCTION: P53, as a tumor suppressor gene, is believed to be one of the most mutated genes in cancer cells. The mutant forms of this protein often play a tumorigenic role in cancer cells. Recent evidence shows that p53 plays a critical role in the migration, metastasis, and invasion of cancer cells. The present article aims to investigate the molecular mechanism that induces metastasis in cancer cells generated by the mutant P53, and to highlight the compounds targeting mutant-p53 together with their clinical applications.METHODS: A detailed literature search was conducted to find information about the role of the mutant-p53 in the processes involved in metastasis in various databases.
RESULTS: A growing body of evidence suggests that Mutant-p53 enhances tumor metastasis affecting the Epithelial-mesenchymal transition (EMT) process, cancer stem cells, angiogenesis, autophagy, anoikis, and any other mechanisms regarding metastasis.
CONCLUSIONS: Taken together, targeting mutant-p53 by altering the processes involved in metastasis could be a potential therapeutic strategy in the treatment of metastatic cancer.

Keywords:  Angiogenesis; Anoikis; Autophagy; Cancer stem cells; EMT; Metastasis; Mutant p53

DOI:  https://doi.org/10.1007/s11033-021-06706-1
Cancer Lett. 2021 Sep 08. pii: S0304-3835(21)00427-4. [Epub ahead of print]521 252-267

Celastrol in cancer therapy: Recent developments, challenges and prospects.

Hannah Ying Lim, Pei Shi Ong, Lingzhi Wang, Arul Goel, Lingwen Ding, Andrea Li-Ann Wong, Paul Chi-Lui Ho, Gautam Sethi, Xiaoqiang Xiang, Boon Cher Goh.

  Cancer is one of the world's biggest healthcare burdens and despite the current advancements made in treatment plans, the outcomes for oncology patients have yet to reach their full potential. Hence, there is a pressing need to develop novel anti-cancer drugs. A popular drug class for research are natural compounds, due to their multi-targeting potential and enhanced safety profile. One such promising natural bioactive compound derived from a vine, Tripterygium wilfordii is celastrol. Pre-clinical studies revolving around the use of celastrol have revealed positive pharmacological activities in various types of cancers, thus suggesting the chemical's potential anti-cancerous effects. However, despite the numerous preclinical studies carried out over the past few decades, celastrol has not reached human trials for cancer. In this review, we summarize the mechanisms and therapeutic potentials of celastrol in treatment for different types of cancer. Subsequently, we also explore the possible reasons hindering its development for human use as cancer therapy, like its narrow therapeutic window and poor pharmacokinetic properties. Additionally, after critically analysing both in vitro and in vivo evidence, we discuss about the key pathways effected by celastrol and the suitable types of cancer that can be targeted by the natural drug, thus giving insight into future directions that can be taken, such as in-depth analysis and research of the druggability of celastrol derivatives, to aid the clinical translation of this promising anti-cancer lead compound.

Keywords:  Anti-cancer activity; Celastrol; Pharmacokinetics; Toxicity; Translational potential

DOI:  https://doi.org/10.1016/j.canlet.2021.08.030
Mol Cancer Ther. 2021 Sep 13. pii: molcanther.0201.2021. [Epub ahead of print]

Characterization of KRAS Mutation Subtypes in Non-Small Cell Lung Cancer.

Julia Judd, Nagla Abdel Karim, Hina Khan, Abdul Rafeh Naqash, Yasmine Baca, Joanne Xiu, Ari M VanderWalde, Hirva Mamdani, Luis E Raez, Misako Nagasaka, Sachin Gopalkrishna Pai, Mark Socinski, Jorge J Nieva, Chul Kim, Antoinette J Wozniak, Chukwuemeka Ikpeazu, Gilberto de Lima Lopes, Alexander I Spira, W Michael Korn, Edward S Kim, Stephen V Liu, Hossein Borghaei.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS mutated NSCLC in a large national cohort to help guide future therapeutic development. Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing (NGS) of 592 genes (Caris Life Sciences) and classified based on presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB) and PD-L1 expression (22C3, TPS score) were analyzed by KRAS mutation type. Across the cohort, 4706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (> 10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS > 1%) and PD-L1 high (41.3% TPS > 50%). STK11 was mutated in 8.6% of KRAS wild type NSCLC but more frequent in KRAS mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild type NSCLC (73.6%). KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0201
Cancer Res. 2021 Sep 13. pii: canres.3242.2020. [Epub ahead of print]

Oxidative phosphorylation is a metabolic vulnerability in chemotherapy-resistant triple negative breast cancer.

Kurt W Evans, Erkan Yuca, Stephen S Scott, Ming Zhao, Natalia Paez Arango, Christian X Cruz Pico, Turcin Saridogan, Maryam Shariati, Caleb A Class, Christopher A Bristow, Christopher P Vellano, Xiaofeng Zheng, Ana Maria Gonzalez-Angulo, Xiaoping Su, Coya Tapia, Ken Chen, Argun Akcakanat, Bora Lim, Debu Tripathy, Timothy A Yap, Maria Emilia Di Francesco, Giulio F Draetta, Philip Jones, Timothy P Heffernan, Joseph R Marszalek, Funda Meric-Bernstam.

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pre-treatment biopsies from patients with triple negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of an OXPHOS signature. In multiple TNBC patient-derived xenografts (PDXs), treatment with IACS-10759, a novel inhibitor of OXPHOS, stabilized tumor growth. Gene expression profiling revealed that all sensitive models displayed a basal-like 1 TNBC subtype, and expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen in tumors treated with IACS-10759 found several potential synthetic lethal targets, including CDK4. A combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 exhibited significant anti-tumor efficacy in vitro and in vivo. In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy compared to either single agent. Taken together, these data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3242
NPJ Syst Biol Appl. 2021 Sep 17. 7(1): 36

Argininosuccinate lyase is a metabolic vulnerability in breast development and cancer.

Sigurdur Trausti Karvelsson, Qiong Wang, Bylgja Hilmarsdottir, Arnar Sigurdsson, Siver Andreas Moestue, Gunhild Mari Mælandsmo, Skarphedinn Halldorsson, Steinn Gudmundsson, Ottar Rolfsson.

Epithelial-to-mesenchymal transition (EMT) is fundamental to both normal tissue development and cancer progression. We hypothesized that EMT plasticity defines a range of metabolic phenotypes and that individual breast epithelial metabolic phenotypes are likely to fall within this phenotypic landscape. To determine EMT metabolic phenotypes, the metabolism of EMT was described within genome-scale metabolic models (GSMMs) using either transcriptomic or proteomic data from the breast epithelial EMT cell culture model D492. The ability of the different data types to describe breast epithelial metabolism was assessed using constraint-based modeling which was subsequently verified using 13C isotope tracer analysis. The application of proteomic data to GSMMs provided relatively higher accuracy in flux predictions compared to the transcriptomic data. Furthermore, the proteomic GSMMs predicted altered cholesterol metabolism and increased dependency on argininosuccinate lyase (ASL) following EMT which were confirmed in vitro using drug assays and siRNA knockdown experiments. The successful verification of the proteomic GSMMs afforded iBreast2886, a breast GSMM that encompasses the metabolic plasticity of EMT as defined by the D492 EMT cell culture model. Analysis of breast tumor proteomic data using iBreast2886 identified vulnerabilities within arginine metabolism that allowed prognostic discrimination of breast cancer patients on a subtype-specific level. Taken together, we demonstrate that the metabolic reconstruction iBreast2886 formalizes the metabolism of breast epithelial cell development and can be utilized as a tool for the functional interpretation of high throughput clinical data.

DOI: https://doi.org/10.1038/s41540-021-00195-5
Biochem J. 2021 Sep 17. 478(17): 3373-3393

The roles of epigenetics in cancer progression and metastasis.

Jocelyn F Chen, Qin Yan.

  Cancer metastasis remains a major clinical challenge for cancer treatment. It is therefore crucial to understand how cancer cells establish and maintain their metastatic traits. However, metastasis-specific genetic mutations have not been identified in most exome or genome sequencing studies. Emerging evidence suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the metastatic disease. A variety of epigenetic mechanisms were identified to regulate metastasis, including the well-studied DNA methylation and histone modifications. In the past few years, large scale chromatin structure alterations including reprogramming of the enhancers and chromatin accessibility to the transcription factors were shown to be potential driving force of cancer metastasis. To dissect the molecular mechanisms and functional output of these epigenetic changes, it is critical to use advanced techniques and alternative animal models for interdisciplinary and translational research on this topic. Here we summarize our current understanding of epigenetic aberrations in cancer progression and metastasis, and their implications in developing new effective metastasis-specific therapies.

Keywords:  cancer metastasis; chromatin opening; enhancer reprogramming; epigenetics; histone modification; tumor progression

DOI:  https://doi.org/10.1042/BCJ20210084
Life Sci. 2021 Sep 10. pii: S0024-3205(21)00930-9. [Epub ahead of print] 119943

The glycine betaine role in neurodegenerative, cardiovascular, hepatic, and renal diseases: Insights into disease and dysfunction networks.

Jesús A Rosas-Rodríguez, Elisa M Valenzuela-Soto.

  Glycine betaine (N, N, N-trimethyl amine) is an osmolyte accumulated in cells that is key for cell volume and turgor regulation, is the principal methyl donor in the methionine cycle and is a DNA and proteins stabilizer. In humans, glycine betaine is synthesized from choline and can be obtained from some foods. Glycine betaine (GB) roles are illustrated in chemical, metabolic, agriculture, and clinical medical studies due to its chemical and physiological properties. Several studies have extensively described GB role and accumulation related to specific pathologies, focusing mainly on analyzing its positive and negative role in these pathologies. However, it is necessary to explain the relationship between glycine betaine and different pathologies concerning its role as an antioxidant, ability to methylate DNA, interact with transcription factors and cell receptors, and participate in the control of homocysteine concentration in liver, kidney and brain. This review summarizes the most important findings and integrates GB role in neurodegenerative, cardiovascular, hepatic, and renal diseases. Furthermore, we discuss GB impact on other dysfunctions as inflammation, oxidative stress, and glucose metabolism, to understand their cross-talks and provide reliable data to establish a base for further investigations.

Keywords:  Gene regulation; Glycine betaine; Homocysteine; Protein folding; Redox regulation

DOI:  https://doi.org/10.1016/j.lfs.2021.119943
Int J Biol Sci. 2021 ;17(13): 3456-3475

Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells.

Xuejian Zhou, Feifan Wang, Hongshen Wu, Xianwu Chen, Yan Zhang, Juntao Lin, Yueshu Cai, Jiayong Xiang, Ning He, Zhenghui Hu, Xiaodong Jin.

  Bladder carcinoma is among the top 10 most frequently diagnosed cancer types in the world. As a phytochemical active metabolic, thymoquinone (TQ) is extracted from seeds of Nigella sativa, possessing various biological properties in a wide range of diseases. Moreover, the outstanding anti-cancer effect of TQ is attracting increasing attentions. In certain circumstances, moderate autophagy is regarded to facilitate the adaptation of malignant cells to different stressors. Conversely, closely linked with the mitochondrial membrane potential (MMP) loss, the upregulation of intracellular reactive oxygen species (ROS) is reported to activate the cell apoptosis in many cancer types. Furthermore, the vital effects of microRNAs in the pathological processes of cancer cells have also been confirmed by previous studies. The present research confirms that TQ restrains the viability, proliferation, migration and invasion through activating caspase-dependent apoptosis in bladder carcinoma cells, which is mediated by TQ induced ROS increase in bladder carcinoma cells. Furthermore, TQ is proved to block the fusion of autophagosomes and lysosomes, causing the accumulation of autophagosomes and subsequent cell apoptosis. In addition, TQ is also found to initiate the miR-877-5p/PD-L1 axis, which suppresses the epithelial mesenchymal transition (EMT) and invasion of bladder carcinoma cells. Taken together, TQ induces the apoptosis through upregulating ROS level and impairing autophagic flux, and inhibiting the EMT and cell invasion via activating the miR-877-5p/PD-L1 axis in bladder carcinoma cells.

Keywords:  Autophagic flux; Bladder carcinoma; Epithelial mesenchymal transition; Reactive oxygen specifics; Thymoquinone; miR-877-5p/PD-L1 axis

DOI:  https://doi.org/10.7150/ijbs.60401
Cancer Metab. 2021 Sep 15. 9(1): 32

Brief report: The uricase mutation in humans increases our risk for cancer growth.

Mehdi A Fini, Miguel A Lanaspa, Eric A Gaucher, Brian Boutwell, Takahiko Nakagawa, Richard M Wright, Laura G Sanchez-Lozada, Peter Andrews, Kurt R Stenmark, Richard J Johnson.

  BACKGROUND: Recent studies suggest that fructose, as well as its metabolite, uric acid, have been associated with increased risk for both cancer incidence and growth. Both substances are known to cause oxidative stress to mitochondria and to reduce adenosine triphosphate (ATP) production by blocking aconitase in the Krebs cycle. The uricase mutation that occurred in the Miocene has been reported to increase serum uric acid and to amplify the effects of fructose to stimulate fat accumulation. Here we tested whether the uricase mutation can also stimulate tumor growth.METHODS: Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks.
RESULTS: The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth.
CONCLUSION: A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.

Keywords:  Fructose; Obesity; Thrifty gene; Tumor growth; Uric acid; Uricase

DOI:  https://doi.org/10.1186/s40170-021-00268-3
Anticancer Agents Med Chem. 2021 Sep 09.

Molecular and Metabolomic Investigation of Celecoxib Antiproliferative Activity in Mono-and Combination Therapy Against Breast Cancer Cell Models.

Sanaa K Bardaweel, Lina A Dahabiyeh, Bushra M Akileh, Dana D Shalabi, Afnan K AlHiary, Judy Pawling, James W Dennis, Anas M Abdel Rahman.

  BACKGROUND: Chronic inflammation plays a crucial role in the initiation, promotion, and invasion of tumors, and thus the antiproliferative effects of numerous anti-inflammatory drugs have been frequently reported in the literature. Upregulation of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) has been linked to various human cancers, including breast cancer.OBJECTIVES: This research aims to investigate the antiproliferative activity of different Non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective and non-selective agents, against various breast cancer cell lines and to elucidate possible molecular pathways involved in their activity.
METHODS: The antiproliferative and combined effects of NSAIDs with raloxifene were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. A mass spectrometry-based targeted metabolomics approach was used to profile the metabolomic changes induced in the T47d cells upon drug treatment.
RESULTS: Our results have demonstrated that celecoxib, a potent and selective COX-2 inhibitor, resulted in significant antiproliferative activity against all examined breast cancer cell lines with IC50 values of 95.44, 49.50. and 97.70 μM against MDA-MB-231, T47d, and MCF-7, respectively. Additionally, celecoxib exhibited a synergistic effect against T47d cells combined with raloxifene, a selective estrogen receptor modulator. Interestingly, celecoxib treatment increased cell apoptosis and resulted in substantial inhibition of cancer cell migration. In addition, the metabolomic analysis suggests that celecoxib may have affected metabolites (n = 43) that are involved in several pathways, including the tricarboxylic acid cycle, amino acids metabolism pathways, and energy production pathways in cancer cells.
CONCLUSION: Celecoxib may possess potential therapeutic utility for breast cancer treatment as monotherapy or in combination therapy. The reported metabolic changes taking place upon celecoxib treatment may shed light on possible molecular targets mediating the antiproliferative activity of celecoxib in an independent manner of its COX-2 inhibition.

Keywords:  Breast cancer; NSAIDs; celecoxib; combination therapy; metabolomics; raloxifene

DOI:  https://doi.org/10.2174/1871520621666210910101349
Int J Nanomedicine. 2021 ;16 6035-6048

Elemene Nanoemulsion Inhibits Metastasis of Breast Cancer by ROS Scavenging.

Bo Han, Tao Wang, Zhigang Xue, Tao Wen, Ling Lu, Jie Meng, Jian Liu, Sizhu Wu, Jianchun Yu, Haiyan Xu.

  Introduction: Elemene (C15H24) is a sesquiterpene compound extracted from the rhizome of Curcuma herbs. In the past decades, the anti-tumor activity of elemene has been observed in vitro and in some clinical practices. However, pharmacological mechanisms of elemene are not demonstrated adequately, which may lead to improper clinical applications. This study aimed to investigate the anti-tumor effect of elemene nanoemulsion in the mouse model of triple-negative breast cancer (TNBC) and reveal the underlying mechanisms.Methods: The ESR measurement and quantum mechanics simulation were used to characterize the antioxidant ability of elemene nanoemulsion. The murine breast cancer cell line 4T1 cells were inoculated subcutaneously into the left fourth mammary fat pad of BalB/c mice to establish a TNBC mice model. The H&E staining, immunohistochemical staining, DHE staining and Western blot were employed to evaluate the therapeutic effects of the elemene nanoemulsion on the TNBC mice.
Results: It was shown that the elemene nanoemulsion prolonged the survival of the triple-negative breast cancer-bearing mice and inhibited the metastasis to lung and liver while did not induce significant cytotoxicity to the tumor cells. Mechanistic studies demonstrated that the elemene nanoemulsion effectively scavenged the reactive oxygen species (ROS) in vitro and in vivo, which decreased the stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently reduced angiogenesis in the tumor microenvironment as well as decreased the level of NLRP3 inflammasomes and IL-1β production. In addition, the elemene nanoemulsion downregulated the level of IL-1β in the RAW264.7 cells in exposure with LPS.
Conclusion: In conclusion, due to the ROS scavenging ability, elemene nanoemulsion effectively inhibited the metastasis of the breast cancer cells to lung and liver and consequently prolonged the survival of TNBC mice.

Keywords:  ROS; breast cancer; elemene; macrophages; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S327094