bims-glucam 2022-01-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–01–02
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Curcumin Synergizes with Cisplatin to Inhibit Colon Cancer through Targeting the MicroRNA-137-Glutaminase Axis.
Glutamine promotes the generation of B10+ cells via the mTOR/GSK3 pathway.
Neutrophil metabolism in the cancer context.
New insights into the molecular mechanisms of glutaminase C inhibitors in cancer cells using serial room temperature crystallography.
Yap-Myc signaling induces pancreatic stellate cell activation through regulating glutaminolysis.
Impact of cancer metabolism on therapy resistance - Clinical implications.
Macrophages are metabolically heterogeneous within the tumor microenvironment.
Metabolic response to radiation therapy in cancer.
A cell culture platform for quantifying metabolic substrate oxidation in bicarbonate-buffered medium.

Curr Med Sci. 2021 Dec 26.

Curcumin Synergizes with Cisplatin to Inhibit Colon Cancer through Targeting the MicroRNA-137-Glutaminase Axis.

Wen-Hui Fan, Feng-Chun Wang, Zhi Jin, Lin Zhu, Jian-Xin Zhang.

   OBJECTIVE: Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies world-wide. Currently, surgery, radiotherapy and chemotherapy are clinically applied as common approaches for CRC patients. Cisplatin is one of the most frequently used chemotherapy drugs for diverse cancers. Although chemotherapeutic strategies have improved the prognosis and survival of cancer patients, development of cisplatin resistance has led to cancer recurrence. Curcumin, isolated from turmeric, has been used as an effective anti-cancer agent. However, the molecular mechanisms for curcumin-mediated cisplatin sensitivity of CRC have not been elucidated. This study aimed to investigate the effects of curcumin treatment on cisplatin-resistant CRC cells.
METHODS: Expression levels of miRNAs and mRNAs were determined by qRT-PCR. Protein expression levels were detected by Western blotting. Cell responses to curcumin treatments were evaluated by MTT assay, Clonogenic assay and Annexin V apoptosis assay. The glutamine metabolism of colon cancer cells was assessed by glutamine uptake and glutaminase (GLS) activity. The binding of miR-137 on 3' UTR of GLS was validated by Western blotting and luciferase assay.
RESULTS: Results demonstrated that curcumin significantly synergized with cisplatin (combination index <1) to suppress proliferation of colon cancer cells compared with curcumin or cisplatin alone. Moreover, from the established cisplatin-resistant cell line (HT-29), glutamine metabolism was remarkedly elevated in cisplatin-resistant CRC cells that displayed a glutamine addictive phenotype. Furthermore, curcumin treatments attenuated glutamine metabolism in colon cancer cells. Under low glutamine supply, colon cancer cells showed less sensitivity to curcumin. Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3' UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition.
CONCLUSION: Collectively, these results indicate that curcumin could be clinically applied as an anti-chemoresistance approach against CRC by modulating miR-137-inhibited glutamine metabolism.

Keywords:  cisplatin resistant; curcumin; glutaminase; glutamine metabolism; microRNA-137

DOI:  https://doi.org/10.1007/s11596-021-2469-0
Eur J Immunol. 2021 Dec 27.

Glutamine promotes the generation of B10+ cells via the mTOR/GSK3 pathway.

Julie Mielle, Jacques Morel, Jamila ElHmioui, Bernard Combe, Laurence Macia, Valérie Dardalhon, Naomi Taylor, Rachel Audo, Claire Daien.

  Alterations in cell metabolism can shift the differentiation of immune cells towards a regulatory or inflammatory phenotype, thus opening up new therapeutic opportunities for immune-related diseases. Indeed, growing knowledge on T cell metabolism has revealed differences in the metabolic programs of suppressive regulatory T cells (Tregs) as compared to inflammatory Th1 and Th17 cells. In addition to Tregs, IL-10-producing regulatory B cells are crucial for maintaining tolerance, inhibiting inflammation and autoimmunity. Yet, the metabolic networks regulating diverse B lymphocyte responses are not well known. Here, we show that glutaminase blockade decreased downstream mTOR activation and attenuated IL-10 secretion. Direct suppression of mTOR activity by rapamycin selectively impaired IL-10 production by B cells whereas secretion was restored upon GSK3 inhibition. Mechanistically, we found mTORC1 activation leads to GSK3 inhibition, identifying a key signalling pathway regulating IL-10 secretion by B lymphocytes. Thus, our results identify glutaminolysis and the mTOR/GSK3 signalling axis, as critical regulators of the generation of IL-10 producing B cells with regulatory functions. This article is protected by copyright. All rights reserved.

Keywords:  B10; GSK3; IL-10; glutamine; immunotherapy; mTOR; metabolism; regulatory B cells

DOI:  https://doi.org/10.1002/eji.202149387
Semin Immunol. 2021 Dec 25. pii: S1044-5323(21)00114-7. [Epub ahead of print] 101583

Neutrophil metabolism in the cancer context.

Anita Bodac, Etienne Meylan.

  Neutrophils are critical innate immune cells for the host anti-bacterial defense. Throughout their lifecycle, neutrophils are exposed to different microenvironments and modulate their metabolism to survive and sustain their functions. Although tumor cell metabolism has been intensively investigated, how neutrophil metabolism is affected in cancer remains largely to be discovered. Neutrophils are described as mainly glycolytic cells. However, distinct tumor-associated neutrophil (TAN) states may co-exist in tumors and adapt their metabolism to exert different or even opposing activities ranging from tumor cell killing to tumor support. In this review, we gather evidence about the metabolic mechanisms that underly TANs' pro- or anti-tumoral functions in cancer. We first discuss how tumor-secreted factors and the heterogenous tumor microenvironment can have a strong impact on TAN metabolism. We then describe alternative metabolic pathways used by TANs to exert their functions in cancer, from basic glycolysis to more recently-recognized but less understood metabolic shifts toward mitochondrial oxidative metabolism, lipid and amino acid metabolism and even autophagy. Last, we discuss promising strategies targeting neutrophil metabolism to combat cancer.

Keywords:  Cancer metabolism; Neutrophil metabolism; Tumor-associated neutrophils

DOI:  https://doi.org/10.1016/j.smim.2021.101583
J Biol Chem. 2021 Dec 23. pii: S0021-9258(21)01345-4. [Epub ahead of print] 101535

New insights into the molecular mechanisms of glutaminase C inhibitors in cancer cells using serial room temperature crystallography.

Shawn K Milano, Qingqiu Huang, Thuy-Tien T Nguyen, Sekar Ramachandran, Aaron Finke, Irina Kriksunov, David Schuller, Marian Szebenyi, Elke Arenholz, Lee A McDermott, N Sukumar, Richard A Cerione, William P Katt.

  Cancer cells frequently exhibit uncoupling of the glycolytic pathway from the TCA cycle (i.e. the "Warburg effect"), and as a result, often become dependent on their ability to increase glutamine catabolism. The mitochondrial enzyme Glutaminase C (GAC) helps to satisfy this 'glutamine addiction' of cancer cells by catalyzing the hydrolysis of glutamine to glutamate, which is then converted to the TCA-cycle intermediate α-ketoglutarate. This makes GAC an intriguing drug target, and spurred the molecules derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (the so-called BPTES-class of allosteric GAC inhibitors), including CB-839, which is currently in clinal trials. However, none of the drugs targeting GAC are yet approved for cancer treatment and their mechanism of action is not well understood. Here, we shed new light on the underlying basis for the differential potencies exhibited by members of the BPTES/CB-839 family of compounds, which could not previously be explained with standard cryo-cooled X-ray crystal structures of GAC bound to CB-839 or its analogs. Using an emerging technique known as serial room temperature crystallography, we were able to observe clear differences between the binding conformations of inhibitors with significantly different potencies. We also developed a computational model to further elucidate the molecular basis of differential inhibitor potency. We then corroborated the results from our modeling efforts using recently established fluorescence assays that directly read out inhibitor binding to GAC. Together, these findings should aid in future design of more potent GAC inhibitors with better clinical outlook.

Keywords:  anti-cancer drugs; cancer; cell metabolism; crystallography; glutaminase

DOI:  https://doi.org/10.1016/j.jbc.2021.101535
Exp Cell Res. 2021 Dec 25. pii: S0014-4827(21)00556-5. [Epub ahead of print]411(1): 113000

Yap-Myc signaling induces pancreatic stellate cell activation through regulating glutaminolysis.

Dong Zhang, Lin Zhao, Minna Luo, Jianjun Lei, Shan Shao.

  The accumulation of activated myofibroblastic pancreatic stellate cells (MF-PSCs) induces pancreatic cancer desmoplasia. These MF-PSCs are derived from quiescent pancreatic stellate cells (Q-PSCs). MF-PSCs in pancreatic cancer tend to glycolysis. However, increased glycolysis alone could not be sufficient for the increased metabolic demands of MF-PSCs. Yap and Myc signaling activation is involved in pancreatic cancer metabolism. Since elucidating the metabolic processes of MF-PSCs may be a promising strategy to suppress pancreatic cancer desmoplasia, we explored whether glutaminolysis meets the bioenergetic and biosynthetic demands of Q-PSCs converted into MF-PSCs and whether this is mediated by Yap signaling to Myc. In this study, we found that during the transdifferentiation of Q-PSCs into MF-PSCs, glutaminolysis regulatory genes were upregulated, and suppression of glutaminolysis inhibited transdifferentiation. Disrupting glutaminolysis in MF-PSCs inhibited cell growth, mitochondrial respiration, and fibrogenesis, while treatment of MF-PSCs with DKG (a glutaminolysis metabolite) reversed these activities. The expression of glutaminase (GLS1), a rate-limiting enzyme in glutaminolysis, was upregulated by Yap overexpression. Yap upregulates Myc to regulate the expression of GLS1 in MF-PSCs. Yap and Myc inhibitors disrupted glutaminolysis and inhibited myofibroblastic activities in PSCs. Thus, Yap-Myc signaling controls glutaminolysis to activate PSCs and might be a therapeutic target for pancreatic cancer desmoplasia.

Keywords:  Desmoplasia; Glutaminolysis; Pancreatic cancer; Yap-Myc signaling

DOI:  https://doi.org/10.1016/j.yexcr.2021.113000
Drug Resist Updat. 2021 Dec 16. pii: S1368-7646(21)00057-1. [Epub ahead of print] 100797

Impact of cancer metabolism on therapy resistance - Clinical implications.

Ana Cristina Gonçalves, Elena Richiardone, Joana Jorge, Bárbara Polónia, Cristina P R Xavier, Iris Chiara Salaroglio, Chiara Riganti, M Helena Vasconcelos, Cyril Corbet, Ana Bela Sarmento-Ribeiro.

  Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.

Keywords:  Cancer metabolism; Glycolysis; Intratumor heterogeneity; Metabolic plasticity; Oxidative phosphorylation; Therapy resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.drup.2021.100797
Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01671-5. [Epub ahead of print]37(13): 110171

Macrophages are metabolically heterogeneous within the tumor microenvironment.

Xenia Geeraerts, Juan Fernández-Garcia, Felix J Hartmann, Kyra E de Goede, Liesbet Martens, Yvon Elkrim, Ayla Debraekeleer, Benoit Stijlemans, Anke Vandekeere, Gianmarco Rinaldi, Riet De Rycke, Mélanie Planque, Dorien Broekaert, Elisa Meinster, Emile Clappaert, Pauline Bardet, Aleksandar Murgaski, Conny Gysemans, Frank Aboubakar Nana, Yvan Saeys, Sean C Bendall, Damya Laoui, Jan Van den Bossche, Sarah-Maria Fendt, Jo A Van Ginderachter.

  Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.

Keywords:  TCA cycle break; immunometabolism; immunosuppression; lactate; macrophage metabolism; metabolomics; non-small-cell lung carcinoma; single-cell metabolic profiling; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2021.110171
Mol Carcinog. 2021 Dec 27.

Metabolic response to radiation therapy in cancer.

Graham H Read, Justine Bailleul, Erina Vlashi, Aparna H Kesarwala.

  Tumor metabolism has emerged as a hallmark of cancer and is involved in carcinogenesis and tumor growth. Reprogramming of tumor metabolism is necessary for cancer cells to sustain high proliferation rates and enhanced demands for nutrients. Recent studies suggest that metabolic plasticity in cancer cells can decrease the efficacy of anticancer therapies by enhancing antioxidant defenses and DNA repair mechanisms. Studying radiation-induced metabolic changes will lead to a better understanding of radiation response mechanisms as well as the identification of new therapeutic targets, but there are few robust studies characterizing the metabolic changes induced by radiation therapy in cancer. In this review, we will highlight studies that provide information on the metabolic changes induced by radiation and oxidative stress in cancer cells and the associated underlying mechanisms.

Keywords:  cancer; metabolism; oxidative stress; radiation therapy; radiosensitivity

DOI:  https://doi.org/10.1002/mc.23379
J Biol Chem. 2021 Dec 28. pii: S0021-9258(21)01357-0. [Epub ahead of print] 101547

A cell culture platform for quantifying metabolic substrate oxidation in bicarbonate-buffered medium.

James R Krycer, Mary Lor, Rebecca L Fitzsimmons, James E Hudson.

  Complex diseases such as cancer and diabetes are underpinned by changes in metabolism, specifically by which and how nutrients are catabolized. Substrate utilization can be directly examined by measuring a metabolic endpoint rather than an intermediate (such as tricarboxylic cycle metabolite). For instance, oxidation of specific substrates can be measured in vitro by incubation of live cultures with substrates containing radiolabeled carbon and measuring radiolabeled carbon dioxide. To increase throughput, we previously developed a miniaturized platform to measure substrate oxidation of both adherent and suspension cells using multiwell plates rather than flasks. This enabled multiple conditions to be examined simultaneously, ideal for drug screens and mechanistic studies. However, like many metabolic assays, this was not compatible with bicarbonate-buffered media, which is susceptible to alkalinization upon exposure to gas containing little carbon dioxide such as air. While other buffers such as HEPES can overcome this problem, bicarbonate has additional biological roles as a metabolic substrate and in modulating hormone signaling. Here, we create a bicarbonate-buffered well-plate platform to measure substrate oxidation. This was achieved by introducing a sealed environment within each well that was equilibrated with carbon dioxide, enabling bicarbonate buffering. As proof of principle, we assessed metabolic flux in cultured adipocytes, demonstrating that bicarbonate-buffered medium increased lipogenesis, glucose oxidation, and sensitivity to insulin in comparison to HEPES-buffered medium. This convenient and high-throughput method facilitates the study and screening of metabolic activity under more physiological conditions to aid biomedical research.

Keywords:  Gas trap; adipocyte; bicarbonate; carbon dioxide; cell metabolism; glucose; oxidation

DOI:  https://doi.org/10.1016/j.jbc.2021.101547