bims-kracam 2021-06-13 papers

on K-Ras in cancer metabolism

Issue of 2021‒06‒13
eleven papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development

The Bidirectional Relationship Between Cancer Epigenetics and Metabolism.
Interaction between RAS gene and lipid metabolism in cancer.
High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.
Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition.
Targeting pyruvate kinase muscle isoform 2 (PKM2) in cancer: What do we know so far?
Amino acid transporters as emerging therapeutic targets in cancer.
Arginine Metabolism and Its Potential in Treatment of Colorectal Cancer.
Cellular Stress Responses and Metabolic Reprogramming in Cancer Progression and Dormancy.
Metabolic reprograming of antioxidant defense: a precision medicine perspective for radiotherapy of lung cancer?
Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma.
PPFIA4 Promotes Colon Cancer Cell Proliferation and Migration by Enhancing Tumor Glycolysis.

Annu Rev Cancer Biol. 2021 Mar;5(1): 235-257

The Bidirectional Relationship Between Cancer Epigenetics and Metabolism.

Luke T Izzo, Hayley C Affronti, Kathryn E Wellen.

  Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.

Keywords:  cancer; cell metabolism; chromatin modification; epigenetics

DOI:  https://doi.org/10.1146/annurev-cancerbio-070820-035832
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Feb 25. 50(1): 17-22

Interaction between RAS gene and lipid metabolism in cancer.

Junchen Pan, Mingquan Zhang, Peng Huang.

  The gene is frequently mutated and abnormally activated in many cancers，and plays an important role in cancer development. Metabolic reprogramming occurs in malignant tumors，which can be one of the key targets for anti-tumor therapy. gene can regulate lipid metabolism through AKT-mTORC1 single axis or multiple pathways，such as lipid synthesis pathways and degradation pathways. Similarly，lipid metabolism can also modify and activate RAS protein and its downstream signaling pathways. This article overviews the current research progress on the interaction between lipid metabolism and ，to provide insight in therapeutic strategies of lipid metabolism for -driven tumors.

Keywords:  Lipid metabolism; Review; Therapy; Tumor; gene

DOI:  https://doi.org/10.3724/zdxbyxb-2021-0054
Cell Rep. 2021 Jun 08. pii: S2211-1247(21)00562-3. [Epub ahead of print]35(10): 109212

High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.

Miyeko D Mana, Amanda M Hussey, Constantine N Tzouanas, Shinya Imada, Yesenia Barrera Millan, Dorukhan Bahceci, Dominic R Saiz, Anna T Webb, Caroline A Lewis, Peter Carmeliet, Maria M Mihaylova, Alex K Shalek, Ömer H Yilmaz.

  Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.

Keywords:  Apc; Cpt1a; Ppar; fatty acid oxidation; high-fat diet; intestinal stem cells

DOI:  https://doi.org/10.1016/j.celrep.2021.109212
Cancer Res. 2021 Jun 11. pii: canres.3792.2020. [Epub ahead of print]

Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition.

Liang Yan, Bo Tu, Jun Yao, Jing Gong, Alessandro Carugo, Christopher A Bristow, Qiuyun Wang, Cihui Zhu, Bingbing Dai, Ya'an Kang, Leng Han, Ningping Feng, Yanqing Jin, Jason Fleming, Timothy P Heffernan, Wantong Yao, Haoqiang Ying.

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3792
Life Sci. 2021 Jun 05. pii: S0024-3205(21)00680-9. [Epub ahead of print] 119694

Targeting pyruvate kinase muscle isoform 2 (PKM2) in cancer: What do we know so far?

Abu Sufiyan Chhipa, Snehal Patel.

  Cancer is a leading cause of death globally. Cancer cell transformation is the result of intricate crosstalk between intracellular components and proteins. A characteristic feature of cancer cells is the ability to reprogram their metabolic pathways to ensure their infinite proliferative potential. Pyruvate kinase muscle isoform 2 (PKM2) is a glycolytic enzyme that plays a crucial role in cancer, apart from carrying out its metabolic roles. PKM2 is involved in all the major events associated with cancer growth. Modulation of PKM2 activity (dimer inhibition or tetramer activation) has been successful in controlling cancer. However, recent studies provide contrary evidences regarding the oncogenic functions of PKM2. Moreover, several studies have highlighted the cancerous roles of PKM1 isoform in certain contexts. The present review aims at providing the current updates regarding PKM2 targeting in cancer. Further, the review discusses the contradictory results that suggest that both the isoforms of PKM can lead to cancer growth. In conclusion, the review emphasizes revisiting the approaches to target cancer metabolism through PKM to find novel and effective targets for anticancer therapy.

Keywords:  Cancer; Cancer metabolism; PKM1; PKM2; Pyruvate kinase

DOI:  https://doi.org/10.1016/j.lfs.2021.119694
Cancer Sci. 2021 Jun 06.

Amino acid transporters as emerging therapeutic targets in cancer.

Yasuhiro Saito, Tomoyoshi Soga.

  Amino acids are indispensable nutrients for both normal and cancer cells. Cancer cells are unable to synthesize essential amino acids as well as some non-essential amino acids adequately to support rapid proliferation, and must uptake amino acids from the surroundings. In order to meet the increased demand for amino acids needed for proliferation, high levels of amino acid transporters are expressed on the surface of cancer cells. Cancer cells utilize amino acids to synthesize proteins and nucleotides, as well as to obtain energy. In addition, amino acids are known to play pathological roles in cancer cells. Interestingly, breast cancer cells limit the use of amino acids for cell proliferation according to amino acid availability, which depends on estrogen receptor status. Here, we present a summarized literature review of novel amino acid functions in cancer cells. This review organizes the knowledge available on two amino acid transporters, SLC7A5 and SLC7A11, which are considered essential for breast cancer cell growth in a cell-dependent manner. In particular, we propose the glutamine recycling model to clarify the mechanism underlying aberrant SLC7A5 activation. Finally, we overview the pathological significances of SLC7A5 and SLC7A11 in cancer tissues.

Keywords:  Amino acid transporter; Breast cancer; Cell proliferation; Cystine uptake; Leucine uptake

DOI:  https://doi.org/10.1111/cas.15006
Front Cell Dev Biol. 2021 ;9 658861

Arginine Metabolism and Its Potential in Treatment of Colorectal Cancer.

Tao Du, Junyi Han.

  Colorectal cancer is the leading cause of death from cancer globally. The current treatment protocol still heavily relies on early detection and surgery. The molecular mechanisms underlying development of colorectal cancer are clinically important and determine the prognosis and treatment response. The arginine metabolism pathway is hyperactive in colorectal cancer and several molecules involved in the pathway are potential targets for chemoprevention and targeted colorectal cancer therapy. Endothelial nitric oxide synthase (eNOS), argininosuccinate synthetase and ornithine decarboxylase (ODC) are the main enzymes for arginine metabolism. Limiting arginine-rich meat consumption and inhibiting ODC activity largely reduces polyamine synthesis and the incidence of colorectal cancer. Arginine transporter CAT-1 and Human member 14 of the solute carrier family 6 (SLC6A14) are overexpressed in colorectal cancer cells and contributes to intracellular arginine levels. Human member 9 of the solute carrier family 38 (SLC38A9) serves as a component of the lysosomal arginine-sensing machinery. Pharmaceutical inhibition of single enzyme or arginine transporter is hard to meet requirement of restoring of abnormal arginine metabolic network. Apart from application in early screening for colorectal cancer, microRNA-based therapeutic strategy that simultaneously manipulating multiple targets involved in arginine metabolism brings promising future in the treatment of colorectal cancer.

Keywords:  arginine metabolism; colorectal cancer; signal pathway; stem cells; transporters protein

DOI:  https://doi.org/10.3389/fcell.2021.658861
Semin Cancer Biol. 2021 Jun 04. pii: S1044-579X(21)00172-3. [Epub ahead of print]

Cellular Stress Responses and Metabolic Reprogramming in Cancer Progression and Dormancy.

Kyle K Payne.

  Recurrent disease after prolonged tumor dormancy is a major cause of cancer associated mortality, yet many of the mechanisms that are engaged to initiate dormancy as well as later recurrence remain incompletely understood. It is known that cancer cells initiate adaptation mechanisms to adapt tightly regulated cellular processes to non-optimal growth environments; Recent investigations have begun to elucidate the contribution of these mechanisms to malignant progression, with intriguing studies now defining cellular stress as a key contributor to the development and maintenance of cancer dormancy. This review will discuss our current understanding of stress responses facilitating malignant cell adaptation and metabolic reprogramming to establish tumor dormancy.

Keywords:  Cancer dormancy; Cancer recurrence; Endoplasmic Reticulum stress; Metabolism; Oxidative Stress

DOI:  https://doi.org/10.1016/j.semcancer.2021.06.004
Biochem Soc Trans. 2021 Jun 10. pii: BST20200866. [Epub ahead of print]

Metabolic reprograming of antioxidant defense: a precision medicine perspective for radiotherapy of lung cancer?

Johann Matschke, Safa Larafa, Verena Jendrossek.

  Radiotherapy plays a key role in the management of lung cancer patients in curative and palliative settings. Traditionally, radiotherapy was either given alone or in combination with surgery, classical cytotoxic chemotherapy, or both. Technical and physical innovations achieved during the last two decades have helped to enhance the accuracy of radiotherapy dose delivery and have facilitated geometric radiotherapy individualization. Furthermore, multimodal combinations with molecularly tailored drugs or immunotherapy yielded promising survival benefits in selected patients. Yet high locoregional failure rates and frequent development of metastases still limit the patient outcome. One major obstacle to successful treatment is the high molecular heterogeneity observed in lung cancer. So far, clinical radiotherapy does not routinely use the knowledge on molecular subtypes with regard to therapy individualization and predictive biomarkers are missing. Herein, altered cancer metabolism has attracted novel attention during recent years as it promotes tumor growth and progression as well as resistance to anticancer therapies. The present perspective will exemplarily highlight how clinically relevant molecular subtypes defined by co-occurring somatic mutations in KRAS-driven lung cancer impact the metabolic phenotype of cancer cells, how the metabolic phenotype supports intrinsic radioresistance by the improved antioxidant defense, and also discuss potential subtype-specific actionable metabolic vulnerabilities. Understanding metabolic phenotypes of radioresistance and metabolic bottlenecks of cancer cells undergoing radiotherapy in a cancer-specific context will offer largely unexploited future avenues for biological individualization and optimization of radiotherapy. Transcriptional profiles will provide additional benefit in defining metabolic phenotypes associated with radioresistance, particularly in cases, where such dependencies cannot be identified by specific somatic mutations.

Keywords:  antioxidant defense; irradiation; personalized medicine; radiotherapy; tumor metabolism

DOI:  https://doi.org/10.1042/BST20200866
Sci Rep. 2021 Jun 08. 11(1): 12097

Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma.

Yotsawat Pomyen, Anuradha Budhu, Jittiporn Chaisaingmongkol, Marshonna Forgues, Hien Dang, Mathuros Ruchirawat, Chulabhorn Mahidol, Xin Wei Wang, .

Treatment effectiveness in hepatocellular carcinoma (HCC) depends on early detection and precision-medicine-based patient stratification for targeted therapies. However, the lack of robust biomarkers, particularly a non-invasive diagnostic tool, precludes significant improvement of clinical outcomes for HCC patients. Serum metabolites are one of the best non-invasive means for determining patient prognosis, as they are stable end-products of biochemical processes in human body. In this study, we aimed to identify prognostic serum metabolites in HCC. To determine serum metabolites that were relevant and representative of the tissue status, we performed a two-step correlation analysis to first determine associations between metabolic genes and tissue metabolites, and second, between tissue metabolites and serum metabolites among 49 HCC patients, which were then validated in 408 additional Asian HCC patients with mixed etiologies. We found that certain metabolic genes, tissue metabolites and serum metabolites can independently stratify HCC patients into prognostic subgroups, which are consistent across these different data types and our previous findings. The metabolic subtypes are associated with β-oxidation process in fatty acid metabolism, where patients with worse survival outcome have dysregulated fatty acid metabolism. These serum metabolites may be used as non-invasive biomarkers to define prognostic tumor molecular subtypes for HCC.

DOI: https://doi.org/10.1038/s41598-021-91560-1
Front Oncol. 2021 ;11 653200

PPFIA4 Promotes Colon Cancer Cell Proliferation and Migration by Enhancing Tumor Glycolysis.

Jia Huang, Meiling Yang, Zhaoxia Liu, Xiaoqian Li, Junfeng Wang, Nian Fu, Ting Cao, Xuefeng Yang.

  Dysregulated glycolysis is one of the mechanisms employed by cancer cells to facilitate growth and metastasis. Here we aimed to characterize the PPFIA4 gene, as a glycolysis-related oncogene in promoting the proliferation and migration of colon cancer cells. Using bioinformatical tools including The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA), we found that PPFIA4 expression and methylation levels were higher in colon cancer tissues of different stages than in normal tissues. Higher PPFIA4 level was also positively correlated with poorer survival of patients. PPFIA4 upregulation also correlated with poor prognosis and higher clinical stages of colon cancer patients. Colon cancer cell viability, migration and migration were enhanced after PPFIA4 overexpression. EMT markers and glycolysis were upregulated after PPFIA4 overexpression. PPFIA4 expression was found to be positively correlated with PFKFB3 and ENO2 levels, while knockdown of PFKFB3 and ENO2 reduced cell proliferation, migration, invasion and glycolysis. PPFIA4 upregulation is a potential biomarker in colon cancer which promotes proliferation, migration, invasion and glycolysis. The upregulation of PFKFB3/ENO2 signaling by PPFIA4 is a potential mechanism underlying the oncogenic effects of PPFIA4.

Keywords:  PFKFB3/ENO2; PPFIA4; colon cancer; glycolysis; invasion

DOI:  https://doi.org/10.3389/fonc.2021.653200