bims-glucam 2021-12-12 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021‒12‒12
nine papers selected by
Sreeparna Banerjee
Middle East Technical University

ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS.
Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs).
The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer.
Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy.
Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma.
2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3.
Emerging Role of TCA Cycle-Related Enzymes in Human Diseases.
Cancer-Associated Fibroblasts Promote the Upregulation of PD-L1 Expression Through Akt Phosphorylation in Colorectal Cancer.

Mol Metab. 2021 Dec 01. pii: S2212-8778(21)00268-4. [Epub ahead of print] 101410

ANTIMETABOLIC COOPERATIVITY WITH THE CLINICALLY-APPROVED L-ASPARAGINASE AND TYROSINE KINASE INHIBITORS TO ERADICATE CML STEM CELLS.

Anne Trinh, Raeeka Khamari, Quentin Fovez, François-Xavier Mahon, Béatrice Turcq, Didier Bouscary, Patrice Maboudou, Marie Joncquel, Valérie Coiteux, Nicolas Germain, William Laine, Salim Dekiouk, Sandrine Jean-Pierre, Veronique Maguer-Satta, Bart Ghesquiere, Thierry Idziorek, Bruno Quesnel, Jerome Kluza, Philippe Marchetti.

  Long-term treatment with tyrosine kinase inhibitors (TKI) represents an effective treatment for chronic myeloid leukemia (CML) and discontinuation of TKI therapy is now being proposed to patients with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells underline that new therapeutic strategies are needed to prevent molecular relapses. We investigated metabolic pathways responsible for CML surviving Imatinib exposure and its potential therapeutic utility to improve the efficiency of TKI against CML stem cells. Using complementary cell-based techniques, we demonstrated that TKI suppressed glycolysis in a large panel of BCR-ABL1 + cell lines as well as in primary CD34+ stem-like cells from CML patients. However, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase without inducing predominant CML cell death. Clinically relevant concentrations of TKI render CML progenitors and stem cells susceptible to Kidrolase. The combination of TKI with L-asparaginase reactivated the intinsic apoptotic pathway leading to efficient CML cell death. Thus, targeting glutamine metabolism with the clinically-approved drug Kidrolase, in combination with TKI which suppresses glycolysis, represents an effective and widely applicable therapeutic strategy for eradicating CML stem cells.

Keywords:  LSC; metabolic addiction; metabolic stress; stem-like cells; synthetic lethality

DOI:  https://doi.org/10.1016/j.molmet.2021.101410
Cancers (Basel). 2021 Nov 29. pii: 6001. [Epub ahead of print]13(23):

Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs).

Katharina Koch, Rudolf Hartmann, Abigail Kora Suwala, Dayana Herrera Rios, Marcel Alexander Kamp, Michael Sabel, Hans-Jakob Steiger, Dieter Willbold, Amit Sharma, Ulf Dietrich Kahlert, Jarek Maciaczyk.

  Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.

Keywords:  NMR spectroscopy; ZEB1; cancer stem cells; glioblastoma; glutamine; metabolism; oncometabolites; xCT

DOI:  https://doi.org/10.3390/cancers13236001
Front Pharmacol. 2021 ;12 768861

The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer.

Kha Wai Hon, Syafiq Asnawi Zainal Abidin, Iekhsan Othman, Rakesh Naidu.

  Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.

Keywords:  colorectal cancer; metabolic reprogramming; metabolism; protein kinase; signaling pathways

DOI:  https://doi.org/10.3389/fphar.2021.768861
Cancers (Basel). 2021 Nov 24. pii: 5912. [Epub ahead of print]13(23):

Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy.

Angèle Luby, Marie-Clotilde Alves-Guerra.

  Over the past decade, advances in cancer immunotherapy through PD1-PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

Keywords:  cancer; immune response; immunotherapy; metabolic drug; metabolism

DOI:  https://doi.org/10.3390/cancers13235912
Mol Omics. 2021 Aug 26.

Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma.

Esther A Zaal, Harm-Jan de Grooth, Inge Oudaert, Pieter Langerhorst, Sophie Levantovsky, Gijs J J van Slobbe, Jeroen W A Jansen, Eline Menu, Wei Wu, Celia R Berkers.

During the development of drug resistance, multiple myeloma (MM) cells undergo changes to their metabolism. However, how these metabolic changes can be exploited to improve treatment efficacy is not known. Here we demonstrate that targeting coenzyme Q10 (CoQ) biosynthesis through the mevalonate pathway works in synergy with the proteasome inhibitor bortezomib (BTZ) in MM. We show that gene expression signatures relating to the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) predispose to clinical BTZ resistance and poor prognosis in MM patients. Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.

DOI: https://doi.org/10.1039/d1mo00106j
Nat Commun. 2021 Dec 06. 12(1): 6997

2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.

Boris Pantic, Daniel Ives, Mara Mennuni, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Mikel Muñoz-Oreja, Marina Villar-Fernandez, Thanh-Mai Julie Dang, Lodovica Vergani, Iain G Johnston, Robert D S Pitceathly, Robert McFarland, Michael G Hanna, Robert W Taylor, Ian J Holt, Antonella Spinazzola.

Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication.

DOI: https://doi.org/10.1038/s41467-021-26829-0
Cancers (Basel). 2021 Dec 06. pii: 6142. [Epub ahead of print]13(23):

Metabolic Rewiring Is Essential for AML Cell Survival to Overcome Autophagy Inhibition by Loss of ATG3.

Fatima Baker, Ibrahim H Polat, Khalil Abou-El-Ardat, Islam Alshamleh, Marlyn Thoelken, Daniel Hymon, Andrea Gubas, Sebastian E Koschade, Jonas B Vischedyk, Manuel Kaulich, Harald Schwalbe, Shabnam Shaid, Christian H Brandts.

  Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.

Keywords:  ATG3; acute myeloid leukemia; autophagy; autophagy inhibition; metabolic rewiring

DOI:  https://doi.org/10.3390/cancers13236142
Int J Mol Sci. 2021 Dec 02. pii: 13057. [Epub ahead of print]22(23):

Emerging Role of TCA Cycle-Related Enzymes in Human Diseases.

Woojin Kang, Miki Suzuki, Takako Saito, Kenji Miyado.

  The tricarboxylic acid (TCA) cycle is the main source of cellular energy and participates in many metabolic pathways in cells. Recent reports indicate that dysfunction of TCA cycle-related enzymes causes human diseases, such as neurometabolic disorders and tumors, have attracted increasing interest in their unexplained roles. The diseases which develop as a consequence of loss or dysfunction of TCA cycle-related enzymes are distinct, suggesting that each enzyme has a unique function. This review aims to provide a comprehensive overview of the relationship between each TCA cycle-related enzyme and human diseases. We also discuss their functions in the context of both mitochondrial and extra-mitochondrial (or cytoplasmic) enzymes.

Keywords:  TCA cycle; TCA cycle-related enzymes; calcium oscillations; human diseases; mitochondria

DOI:  https://doi.org/10.3390/ijms222313057
Front Oncol. 2021 ;11 748465

Cancer-Associated Fibroblasts Promote the Upregulation of PD-L1 Expression Through Akt Phosphorylation in Colorectal Cancer.

Yang Gao, Zhao Sun, Junjie Gu, Zhe Li, Xiuxiu Xu, Chunling Xue, Xuechun Li, Lin Zhao, Jianfeng Zhou, Chunmei Bai, Qin Han, Robert Chunhua Zhao.

  Upregulation of immune checkpoint proteins is one of the main mechanisms for tumor immune escape. The expression of programmed death ligand-1 (PD-L1) in colorectal cancer (CRC) is higher than in normal colorectal epithelial tissue, and patients with higher PD-L1 expression have a poorer prognosis. Additionally, PD-L1 expression in CRC is affected by the tumor microenvironment (TME). As a major component of the TME, cancer-associated fibroblasts (CAFs) can act as immune regulators and generate an immunosuppressive tumor microenvironment. Therefore, we speculated that CAFs may be related to the upregulation of PD-L1 in CRC, which leads to tumor immune escape. We found that CAFs upregulate PD-L1 expression in CRC cells through AKT phosphorylation, thereby reducing the killing of CRC cells by peripheral blood mononuclear cells. The ratio of CAFs to CRC cells was positively correlated with AKT phosphorylation and the expression of PD-L1 in CRC in vitro. Consistent with the in vitro results, high CAF content and high expression of PD-L1 were negatively correlated with disease-free survival (DFS) of CRC patients. These results indicate that the upregulation of PD-L1 expression in CRC by CAFs through the activation of Akt is one of the molecular mechanisms of tumor immune escape. Thus, targeted anti-CAF therapy may help improve the efficacy of immunotherapy.

Keywords:  Akt phosphorylation; PD-L1; cancer-associated fibroblasts; colorectal cancer; immune escape

DOI:  https://doi.org/10.3389/fonc.2021.748465