bims-glucam 2023-10-22 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023‒10‒22
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.
Tripartite motif containing 33 demonstrated anticancer effect by degrading c‑Myc: Limitation of glutamine metabolism and proliferation in endometrial carcinoma cells.
Systematic analysis of glutamine metabolism family genes and exploration of the biological role of GPT in colorectal cancer.
Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.
Targeting succinylation-mediated metabolic reprogramming as a potential approach for cancer therapy.
Cancer Metabolism under Limiting Oxygen Conditions.
Combined metabolomic and lipidomic analysis uncovers metabolic profile and biomarkers for papillary thyroid carcinoma.
Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.
Metabolic advantages of regulatory T cells dictated by cancer cells.
Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.
Unlocking the potential of the tumor microenvironment for cancer therapy.
The nuclear factor erythroid 2-related factor 2/p53 axis in breast cancer.

Cancer Metab. 2023 Oct 19. 11(1): 18

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.

Amy K Holt, Arafath K Najumudeen, Tracey J Collard, Hao Li, Laura M Millett, Ashley J Hoskin, Danny N Legge, Eleanor M H Mortensson, Dustin J Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D Hitchings, James Cronin, Owen J Sansom, Ann C Williams, Emma E Vincent.

  BACKGROUND: To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.METHODS: We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.
RESULTS: We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.
CONCLUSIONS: Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.

Keywords:  Aspirin; CB-839; Colorectal cancer; Glutaminase; Metabolic reprogramming; Metabolism

DOI:  https://doi.org/10.1186/s40170-023-00318-y
Cancer Drug Resist. 2023 ;6(3): 547-566

A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.

Hiroshi Kobayashi, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi, Shogo Imanaka.

  Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.

Keywords:  Ferroptosis; glutaminolysis; glycolysis; metabolic vulnerability; ovarian cancer; pentose phosphate pathway

DOI:  https://doi.org/10.20517/cdr.2023.49
Int J Oncol. 2023 Dec;pii: 133. [Epub ahead of print]63(6):

Tripartite motif containing 33 demonstrated anticancer effect by degrading c‑Myc: Limitation of glutamine metabolism and proliferation in endometrial carcinoma cells.

Yue Qi, Ningye Ma, Jin Zhang.

  Tripartite motif containing 33 (TRIM33) has been reported to be involved in various tumor progression. However, its role in endometrial carcinoma (EC) remains to be elucidated. By mining the publicly available databases UALCAN and TIMER, low expression of TRIM33 was found in tumor tissues of EC patients. Clinically, downregulation of TRIM33 in EC tissues was positively correlated with the extensive muscle invasion and poor differentiation grade. In vitro, experiments performed on human HEC‑1‑A and AN3CA cells showed that overexpression of TRIM33 inhibited the proliferation, migration and invasion of EC cells, whereas TRIM33 knockdown resulted in the opposite results. Furthermore, upregulation of TRIM33 significantly inhibited the glutamine uptake and decreased the intracellular glutamate in EC cells, which is evidenced by the reduction of solute carrier family 1 member 5 and glutaminase. In vivo, TRIM33 also dramatically inhibited tumor growth and glutamine metabolism. Additionally, co‑immunoprecipitation assay confirmed the interaction between TRIM33 and c‑Myc. Overexpression of TRIM33 could reduce the protein stability of c‑Myc by promoting its degradation. In addition, upregulation of c‑Myc could reverse the effects of TRIM33 on EC cells. Together, the present study demonstrated that TRIM33 acted as a tumor suppressor in EC, which is manifested in its inhibition of glutamine metabolism and cell growth via promoting c‑Myc protein degradation.

Keywords:  c‑Myc; endometrial carcinoma; glutamine metabolism; tripartite motif containing 33

DOI:  https://doi.org/10.3892/ijo.2023.5581
Aging (Albany NY). 2023 Oct 17. 15

Systematic analysis of glutamine metabolism family genes and exploration of the biological role of GPT in colorectal cancer.

Weiqi Dai, Wenhui Mo, Wenqiang Xu, Dengyu Han, Xuanfu Xu.

  BACKGROUND: Colorectal cancer (CRC) is a malignancy of the digestive system with high incidence rate and mortality, and reliable diagnostic and prognostic markers for CRC are still lacking. Glutamine metabolism is crucial to the occurrence and development of CRC. However, no research has systematically analyzed the biological role of glutamine metabolism-related genes (GMRGs) in CRC.METHODS: We downloaded gene expression data and clinical data of CRC patients from the TCGA database. The UCSC database downloads pan-cancer gene expression data and prognosis data. Characteristic GMRGs were screened out using differential analysis and two types of machine learning (SVM-REF and RandomForest). Single-cell RNA-sequencing data from CRC patients were downloaded from GEO data. ROC curve was used to evaluate the diagnostic value. Kaplan-Meier method and univariate Cox regression analysis were used to evaluate the prognostic value. The oncopredict package is used to calculate IC50 values for common drugs in CRC patients.
RESULTS: A total of 31 differentially expressed GMRGs were identified, 9 of which were identified as characteristic GMRGs. Further evaluation of diagnostic and prognostic value finally identified GPT as the most important GMRGs in CRC. scRNA-seq analysis revealed that GPT is almost exclusively expressed in epithelial cells. GPT expression is closely related to the tumor microenvironment and can effectively distinguish the sensitivity of different CRC patients to clinical drugs. In addition, pan-cancer analysis showed that GPT is an excellent diagnostic and prognostic marker for multiple cancers.
CONCLUSIONS: GPT is a reliable diagnostic, prognostic marker and therapeutic target in CRC.

Keywords:  GPT; colorectal cancer; machine learning; scRNA-seq; tumor microenvironment

DOI:  https://doi.org/10.18632/aging.205079
Cancer Drug Resist. 2023 ;6(3): 567-589

Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.

Priyanka Sharma, Gautam Borthakur.

  Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy; we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.

Keywords:  DHODH; IDH; OXPHOS; leukemia stem cells; mesenchymal stromal cells

DOI:  https://doi.org/10.20517/cdr.2023.12
Biomed Pharmacother. 2023 Oct 16. pii: S0753-3322(23)01511-1. [Epub ahead of print]168 115713

Targeting succinylation-mediated metabolic reprogramming as a potential approach for cancer therapy.

Zhenya Liu, Runxian Wang, Yunshan Wang, Yangmiao Duan, Hanxiang Zhan.

  Metabolic reprogramming is a common hallmark of cancers and involves alterations in many metabolic pathways during tumor initiation and progression. However, the cancer-specific modulation of metabolic reprogramming requires further elucidation. Succinylation, a newly identified protein posttranslational modification (PTM), participates in many cellular processes by transferring a succinyl group to a residue of the target protein, which is related to various pathological disorders including cancers. In recent years, there has been a gradual increase in the number of studies on the regulation of tumors by protein succinylation. Notably, accumulating evidence suggests that succinylation can mediate cancer cell metabolism by altering the structure or activity of metabolism-related proteins and plays vital roles in metabolic reprogramming. Furthermore, some antitumor drugs have been linked to succinylation-mediated tumor-associated metabolism. To better elucidate lysine succinylation mediated tumor metabolic reprogramming, this review mainly summarizes recent studies on the regulation and effects of protein succinylation in tumors, focusing on the metabolic regulation of tumorigenesis and development, which will provide new directions for cancer diagnosis as well as possible therapeutic targets.

Keywords:  Cancer; Metabolic reprogramming; PTM; Succinylation; Treatment

DOI:  https://doi.org/10.1016/j.biopha.2023.115713
Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041542. [Epub ahead of print]

Cancer Metabolism under Limiting Oxygen Conditions.

Laura C Kim, Nicholas P Lesner, M Celeste Simon.

Molecular oxygen (O2) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2 Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O2 is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to greater understanding of oxygen-dependent metabolic reprogramming and lead to more effective cancer therapies.

DOI: https://doi.org/10.1101/cshperspect.a041542
Sci Rep. 2023 Oct 17. 13(1): 17666

Combined metabolomic and lipidomic analysis uncovers metabolic profile and biomarkers for papillary thyroid carcinoma.

Zipeng Wang, Yiqin Yang, Yurong Xing, Dandan Si, Suhua Wang, Jiashuo Lin, Cai Li, Ji Zhang, Detao Yin.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy with a rapidly increasing incidence. The pathogenesis of PTC is unclear, but metabolic and lipidomic reprogramming may play a role in tumor growth. We applied ultra-performance liquid chromatography-tandem mass spectrometry to perform widely targeted metabolomics and lipidomics on plasma samples from 94 patients with PTC and 100 healthy controls. We identified 113 differential metabolites and 236 differential lipids, mainly involved in branched-chain amino acid metabolism, glutamate and glutamine metabolism, tricarboxylic acid cycle, and lipid metabolism. We also screened three potential metabolite biomarkers: sebacic acid, L-glutamine, and indole-3-carboxaldehyde. These biomarkers showed excellent diagnostic performance for PTC in both discovery and validation cohorts, with areas under the receiver operating characteristic curves of 0.994 and 0.925, respectively. Our findings reveal distinct metabolic and lipidomic features of PTC and provide novel targets for diagnosis and treatment.

DOI: https://doi.org/10.1038/s41598-023-41176-4
Oncogene. 2023 Oct 18.

Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.

Breelyn Karno, Deanna N Edwards, Jin Chen.

Most cancer-related deaths are caused by the metastases, which commonly develop at multiple organ sites including the brain, bone, and lungs. Despite longstanding observations that the spread of cancer is not random, our understanding of the mechanisms that underlie metastatic spread to specific organs remains limited. However, metabolism has recently emerged as an important contributor to metastasis. Amino acids are a significant nutrient source to cancer cells and their metabolism which can serve to fuel biosynthetic pathways capable of facilitating cell survival and tumor expansion while also defending against oxidative stress. Compared to the primary tumor, each of the common metastatic sites exhibit vastly different nutrient compositions and environmental stressors, necessitating the need of cancer cells to metabolically thrive in their new environment during colonization and outgrowth. This review seeks to summarize the current literature on amino acid metabolism pathways that support metastasis to common secondary sites, including impacts on immune responses. Understanding the role of amino acids in secondary organ sites may offer opportunities for therapeutic inhibition of cancer metastasis.

DOI: https://doi.org/10.1038/s41388-023-02868-3
Int Immunol. 2023 Oct 14. pii: dxad035. [Epub ahead of print]

Metabolic advantages of regulatory T cells dictated by cancer cells.

Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa.

  Cancer cells employ glycolysis for their survival and growth (the 'Warburg effect'). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop 'immune metabolism-based precision medicine'.

Keywords:  metabolism; regulatory T cell

DOI:  https://doi.org/10.1093/intimm/dxad035
iScience. 2023 Oct 20. 26(10): 108059

Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.

Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran.

  Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.

Keywords:  Medical informatics; cancer; computational bioinformatics

DOI:  https://doi.org/10.1016/j.isci.2023.108059
Pathol Res Pract. 2023 Oct 04. pii: S0344-0338(23)00547-2. [Epub ahead of print]251 154846

Unlocking the potential of the tumor microenvironment for cancer therapy.

Muhammad Tufail.

  The tumor microenvironment (TME) holds a crucial role in the progression of cancer. Epithelial-derived tumors share common traits in shaping the TME. The Warburg effect is a notable phenomenon wherein tumor cells exhibit resistance to apoptosis and an increased reliance on anaerobic glycolysis for energy production. Recognizing the pivotal role of the TME in controlling tumor growth and influencing responses to chemotherapy, researchers have focused on developing potential cancer treatment strategies. A wide array of therapies, including immunotherapies, antiangiogenic agents, interventions targeting cancer-associated fibroblasts (CAF), and therapies directed at the extracellular matrix, have been under investigation and have demonstrated efficacy. Additionally, innovative techniques such as tumor tissue explants, "tumor-on-a-chip" models, and multicellular tumor spheres have been explored in laboratory research. This comprehensive review aims to provide insights into the intricate cross-talk between cancer-associated signaling pathways and the TME in cancer progression, current therapeutic approaches targeting the TME, the immune landscape within solid tumors, the role of the viral TME, and cancer cell metabolism.

Keywords:  Cancer cell metabolism; Solid tumors microenvironment; Targeting the tumor microenvironment; Tumor landscape; Tumor mechanics; Viral induced tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2023.154846
Biochem Med (Zagreb). 2023 Oct 15. 33(3): 030504

The nuclear factor erythroid 2-related factor 2/p53 axis in breast cancer.

Lei Xia, Wenbiao Ma, Ahmad Afrashteh, Mir Amirhossein Sajadi, Hadi Fakheri, Mohammad Valilo.

  One of the most important factors involved in the response to oxidative stress (OS) is the nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of components such as antioxidative stress proteins and enzymes. Under normal conditions, Kelch-like ECH-associated protein 1 (Keap1) keeps Nrf2 in the cytoplasm, thus preventing its translocation to the nucleus and inhibiting its role. It has been established that Nrf2 has a dual function; on the one hand, it promotes angiogenesis and cancer cell metastasis while causing resistance to drugs and chemotherapy. On the other hand, Nrf2 increases expression and proliferation of glutathione to protect cells against OS. p53 is a tumour suppressor that activates the apoptosis pathway in aging and cancer cells in addition to stimulating the glutaminolysis and antioxidant pathways. Cancer cells use the antioxidant ability of p53 against OS. Therefore, in the present study, we discussed function of Nrf2 and p53 in breast cancer (BC) cells to elucidate their role in protection or destruction of cancer cells as well as their drug resistance or antioxidant properties.

Keywords:  Kelch-like ECH-associated protein 1 (Keap1); breast cancer; drug resistance; nuclear factor erythroid 2-related factor 2 (Nrf2); p53

DOI:  https://doi.org/10.11613/BM.2023.030504