bims-glucam 2022-10-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒10‒02
eleven papers selected by
Sreeparna Banerjee
Middle East Technical University

Glutamine stabilizes myc via alpha-ketoglutarate and regulates paclitaxel sensitivity.
Transient Systemic Autophagy Inhibition is Selectively and Irreversibly Deleterious to Lung Cancer.
Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway.
Metabolic determinants of stemness in medulloblastoma.
Lithocholic acid inhibits gallbladder cancer proliferation through interfering glutaminase-mediated glutamine metabolism.
Identification of an amino acid metabolism-associated gene signature predicting the prognosis and immune therapy response of clear cell renal cell carcinoma.
An LKB1-mitochondria axis controls TH17 effector function.
Metabolic pathways regulating colorectal cancer: a potential therapeutic approach.
Obesity is associated with altered tumor metabolism in metastatic melanoma.
GOT2 consider the tumor microenvironment.
A critical review of datasets and computational suites for improving cancer theranostics and biomarker discovery.

Med Oncol. 2022 Sep 29. 39(12): 227

Glutamine stabilizes myc via alpha-ketoglutarate and regulates paclitaxel sensitivity.

Vikas Bhardwaj, Jun He, Aditi Jain.

  Metabolic reprogramming wherein the cancer cells exhibit altered energetics is a hallmark of cancer. Although recent discoveries have enhanced our understanding of tumor metabolism, the therapeutic utility of targeting tumor metabolism is not yet realized. Glutamine, a non-essential amino acid, plays a critical role in regulating tumor metabolism and provides an alternative tumor energy source. In this study, we investigate the molecular mechanism regulated by glutamine and elucidate if targeting glutamine metabolism would enhance the efficacy of cancer chemotherapy. Using clonogenic and cell cycle analysis, we found that deprivation of glutamine suppress the growth of cancer cells. Mechanistically we demonstrate that glutamine stabilizes myc by preventing its ubiquitination through alpha-ketoglutarate. Inhibition of glutamine metabolism enhanced the sensitivity of tumor cells to chemotherapeutic agent paclitaxel. Our results delineate the mechanism behind glutamine-induced myc stabilization, and they provide a viable strategy to target cancer with a glutamine metabolism inhibitor in the clinic.

Keywords:  Cancer; Glutamine; Metabolism; Myc

DOI:  https://doi.org/10.1007/s12032-022-01834-5
Cancer Res. 2022 Sep 26. pii: CAN-22-1039. [Epub ahead of print]

Transient Systemic Autophagy Inhibition is Selectively and Irreversibly Deleterious to Lung Cancer.

Khoosheh Khayati, Vrushank Bhatt, Taijin Lan, Fawzi Alogaili, Wenping Wang, Enrique Lopez, Zhixian Sherrie Hu, Samantha Gokhale, Liam Cassidy, Masashi Narita, Ping Xie, Eileen White, Jessie Yanxiang Guo.

Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53-/- (KP) non-small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T cell infiltration, leading to T cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1039
Sci Adv. 2022 Sep 30. 8(39): eabq0117

Mitochondrial pyruvate supports lymphoma proliferation by fueling a glutamate pyruvate transaminase 2-dependent glutaminolysis pathway.

Peng Wei, Alex J Bott, Ahmad A Cluntun, Jeffrey T Morgan, Corey N Cunningham, John C Schell, Yeyun Ouyang, Scott B Ficarro, Jarrod A Marto, Nika N Danial, Ralph J DeBerardinis, Jared Rutter.

The fate of pyruvate is a defining feature in many cell types. One major fate is mitochondrial entry via the mitochondrial pyruvate carrier (MPC). We found that diffuse large B cell lymphomas (DLBCLs) consume mitochondrial pyruvate via glutamate-pyruvate transaminase 2 to enable α-ketoglutarate production as part of glutaminolysis. This led us to discover that glutamine exceeds pyruvate as a carbon source for the tricarboxylic acid cycle in DLBCLs. As a result, MPC inhibition led to decreased glutaminolysis in DLBCLs, opposite to previous observations in other cell types. We also found that MPC inhibition or genetic depletion decreased DLBCL proliferation in an extracellular matrix (ECM)-like environment and xenografts, but not in a suspension environment. Moreover, the metabolic profile of DLBCL cells in ECM is markedly different from cells in a suspension environment. Thus, we conclude that the synergistic consumption and assimilation of glutamine and pyruvate enables DLBCL proliferation in an extracellular environment-dependent manner.

DOI: https://doi.org/10.1126/sciadv.abq0117
World J Stem Cells. 2022 Aug 26. 14(8): 587-598

Metabolic determinants of stemness in medulloblastoma.

Paula Martín-Rubio, Pilar Espiau-Romera, Alba Royo-García, Laia Caja, Patricia Sancho.

  Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glut athione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.

Keywords:  Cancer stem cells; Glycolysis; Lipids; Medulloblastoma; Metabolism; Stemness

DOI:  https://doi.org/10.4252/wjsc.v14.i8.587
Biochem Pharmacol. 2022 Sep 19. pii: S0006-2952(22)00347-1. [Epub ahead of print]205 115253

Lithocholic acid inhibits gallbladder cancer proliferation through interfering glutaminase-mediated glutamine metabolism.

Weijian Li, Zeyu Wang, Ruirong Lin, Shuai Huang, Huijie Miao, Lu Zou, Ke Liu, Xuya Cui, Ziyi Wang, Yijian Zhang, Chengkai Jiang, Shimei Qiu, Jiyao Ma, Wenguang Wu, Yingbin Liu.

  Lithocholic acid (LCA), one of the most common metabolic products of bile acids (BAs), is originally synthesized in the liver, stored in the gallbladder, and released to the intestine, where it assists absorption of lipid-soluble nutrients. LCA has recently emerged as a powerful reagent to inhibit tumorigenesis; however, the anti-tumor activity and molecular mechanisms of LCA in gallbladder cancer (GBC) remain poorly acknowledged. Here, we analyzed serum levels of LCA in human GBC and found that LCA was significantly downregulated in these patients, and reduced LCA levels were associated with poor clinical outcomes. Treatment of xenografts with LCA impeded tumor growth. Furthermore, LCA treatment in GBC cell lines decreased glutaminase (GLS) expression, glutamine (Gln) consumption, and GSH/GSSG and NADPH/NADP+ ratios, leading to cellular ferroptosis. In contrast, GLS overexpression in tumor cells fully restored GBC proliferation and decreased ROS imbalance, thus suppressing ferroptosis. Our findings reveal that LCA functions as a tumor-suppressive factor in GBC by downregulating GLS-mediated glutamine metabolism and subsequently inducing ferroptosis. This study may offer a new therapeutic strategy tailored to improve the treatment of GBC.

Keywords:  Ferroptosis; Gallbladder cancer; Glutaminase; Glutamine; Lithocholic acid; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bcp.2022.115253
Front Oncol. 2022 ;12 970208

Identification of an amino acid metabolism-associated gene signature predicting the prognosis and immune therapy response of clear cell renal cell carcinoma.

Fan Zhang, Junyu Lin, Daiwen Zhu, Yongquan Tang, Yiping Lu, Zhihong Liu, Xianding Wang.

  Background: The upregulation of amino acid metabolism is an essential form of metabolic reprogramming in cancer. Here, we developed an amino acid metabolism signature to predict prognosis and anti-PD-1 therapy response in clear cell renal cell carcinoma (ccRCC).Methods: According to the amino acid metabolism-associated gene sets contained in the Molecular Signature Database, consensus clustering was performed to divide patients into two clusters. An amino acid metabolism-associated signature was identified and verified. Immune cell infiltrates and their corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correspondence between the signature risk score and the immune therapy response.
Results: Two clusters with different amino acid metabolic levels were identified by consensus clustering. The patients in the two clusters differed in overall survival, progression-free survival, amino acid metabolic status, and tumor microenvironment. We identified a signature containing eight amino acid metabolism-associated genes that could accurately predict the prognosis of patients with ccRCC. The signature risk score was positively correlated with infiltration of M1 macrophages, CD8+ T cells, and regulatory T cells, whereas it was negatively correlated with infiltration of neutrophils, NK cells, and CD4+ T cells. Patients with lower risk scores had better overall survival but worse responses to nivolumab.
Conclusion: Amino acid metabolic status is closely correlated with tumor microenvironment, response to checkpoint blockade therapy, and prognosis in patients with ccRCC. The established amino acid metabolism-associated gene signature can predict both survival and anti-PD-1 therapy response in patients with ccRCC.

Keywords:  amino acid metabolism; anti-PD-1 therapy; ccRCC; prognosis; signature

DOI:  https://doi.org/10.3389/fonc.2022.970208
Nature. 2022 Sep 28.

An LKB1-mitochondria axis controls TH17 effector function.

Francesc Baixauli, Klara Piletic, Daniel J Puleston, Matteo Villa, Cameron S Field, Lea J Flachsmann, Andrea Quintana, Nisha Rana, Joy Edwards-Hicks, Mai Matsushita, Michal A Stanczak, Katarzyna M Grzes, Agnieszka M Kabat, Mario Fabri, George Caputa, Beth Kelly, Mauro Corrado, Yaarub Musa, Katarzyna J Duda, Gerhard Mittler, David O'Sullivan, Hiromi Sesaki, Thomas Jenuwein, Joerg M Buescher, Edward J Pearce, David E Sanin, Erika L Pearce.

CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.

DOI: https://doi.org/10.1038/s41586-022-05264-1
Curr Pharm Des. 2022 Sep 22.

Metabolic pathways regulating colorectal cancer: a potential therapeutic approach.

Nima Zafari, Mahla Velayati, Sedigheh Damavandi, Ghazale Pourali, Majid Ghayour Mobarhan, Mohammadreza Nassiri, Seyed Mahdi Hassanian, Majid Khazaei, Gordon A Ferns, Amir Avan.

  Colorectal cancer (CRC) is one of the most prevalent cancers globally. Despite recent progress in identifying etiologies and molecular genetics as well as new therapeutic approaches, the clinical outcome of current CRC therapies remains poor. This fact highlights the importance of further understanding of underlying mechanisms involved in colorectal tumor initiation and progression. Abnormal metabolic alterations offer an evolutional advantage for CRC tumor cells and enhance their aggressive phenotype. Therefore, dysregulation of cellular metabolism is intricately associated with colorectal tumorigenesis. This review summarizes recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism. We describe the oncogenic signaling pathways associated with metabolic dysregulation during malignant transformation and tumor progression. Given the crucial role of metabolic pathway alterations in pathogenesis of CRC, we provide an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.

Keywords:  Colorectal cancer; Glucose metabolism; Metabolic pathways; Metabolic reprogramming; Signaling pathways; Targeted therapies; Warburg effect

DOI:  https://doi.org/10.2174/1381612828666220922111342
Clin Cancer Res. 2022 Sep 27. pii: CCR-22-2661. [Epub ahead of print]

Obesity is associated with altered tumor metabolism in metastatic melanoma.

Andrew W Hahn, Ashley V Menk, Dayana B Rivadeneira, Ryan C Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K Mishra, Tuba N Gide, Camelia Quek, Yan Zang, Christine N Spencer, Alexander M Menzies, Carrie R Daniel, Courtney W Hudgens, Theodore Nowicki, Lauren E Haydu, M A Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M Burton, Jared Malke, Julie M Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E Woodman, Vashisht Gopal Y N, Renato Guerrieri, Grant M Fischer, Jian Wang, Khalida M Wani, John F Thompson, Jeffrey E Lee, Patrick Hwu, Nadim Ajami, Jeffrey E Gershenwald, Georgina V Long, Richard A Scolyer, Michael T Tetzlaff, Alexander J Lazar, Dirk Schadendorf, Jennifer A Wargo, John M Kirkwood, Ralph J DeBerardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S Wilmott, Weiyi Peng, Michael A Davies, Greg M Delgoffe, Yana G Najjar, Jennifer L McQuade.

PURPOSE: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICIs) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient BMI.EXPERIMENTAL DESIGN: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25] and tumor or microbiome characteristics were examined in specimens from 782 metastatic melanoma patients across 7 cohorts. DNA associations were evaluated in the TCGA cohort. RNASeq from 4 cohorts (n=357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x=36) by LC/MS, and in flow-sorted melanoma tumor cells (x=37) and patient-derived melanoma cell lines (x=17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n=371).
RESULTS: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI.
CONCLUSIONS: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2661
Trends Cancer. 2022 Sep 21. pii: S2405-8033(22)00195-9. [Epub ahead of print]

GOT2 consider the tumor microenvironment.

Brian T Do, Matthew G Vander Heiden.

To thrive in a hypoxic and nutrient-limited tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells rewire their metabolism. Understanding PDAC cell metabolism may uncover vulnerabilities that can be targeted for improved therapy. Three recent studies find that the PDAC tumor microenvironment modulates the functional consequences of depleting the mitochondrially localized aspartate transaminase GOT2, thus providing new insights into the metabolism of this lethal cancer.

DOI: https://doi.org/10.1016/j.trecan.2022.09.004
Med Oncol. 2022 Sep 29. 39(12): 206

A critical review of datasets and computational suites for improving cancer theranostics and biomarker discovery.

Gayathri Ashok, Sudha Ramaiah.

  Cancer has been constantly evolving and so is the research pertaining to cancer diagnosis and therapeutic regimens. Early detection and specific therapeutics are the key features of modern cancer therapy. These requirements can only be fulfilled with the integration of diverse high-throughput technologies. Integration of advanced omics methodology involving genomics, epigenomics, proteomics, and transcriptomics provide a clear understanding of multi-faceted cancer. In the past few years, tremendous high-throughput data have been generated from cancer genomics and epigenomic analyses, which on further methodological analyses can yield better biological insights. The major epigenetic alterations reported in cancer are DNA methylation levels, histone post-translational modifications, and epi-miRNA regulating the oncogenes and tumor suppressor genes. While the genomic analyses like gene expression profiling, cancer gene prediction, and genome annotation divulge the genetic alterations in oncogenes or tumor suppressor genes. Also, systems biology approach using biological networks is being extensively used to identify novel cancer biomarkers. Therefore, integration of these multi-dimensional approaches will help to identify potential diagnostic and therapeutic biomarkers. Here, we reviewed the critical databases and tools dedicated to various epigenomic and genomic alterations in cancer. The review further focuses on the multi-omics resources available for further validating the identified cancer biomarkers. We also highlighted the tools for cancer biomarker discovery using a systems biology approach utilizing genomic and epigenomic data. Biomarkers predicted using such integrative approaches are shown to be more clinically relevant.

Keywords:  Cancer Biomarkers; Epigenomics; Gene interaction networks; Genomics; MicroRNA; Multi-omics tools; Systems biology

DOI:  https://doi.org/10.1007/s12032-022-01815-8