bims-glucam 2022-08-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒08‒14
thirteen papers selected by
Sreeparna Banerjee
Middle East Technical University

Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway.
1α,25-dihydroxyvitamin D reduction of MCF10A-ras cell viability in extracellular matrix detached conditions is dependent on regulation of pyruvate carboxylase.
MYC sensitises cells to apoptosis by driving energetic demand.
Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.
Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression.
Glutamine transport as a possible regulator of nitrogen catabolite repression in Saccharomyces cerevisiae.
Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing.
GFAT1-linked TAB1 glutamylation sustains p38 MAPK activation and promotes lung cancer cell survival under glucose starvation.
The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT-20 cells in vitro.
Glutamine deprivation impairs function of infiltrating CD8+ T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis.
Computational Metabolomics Reveals the Potential Mechanism of Matrine Mediated Metabolic Network Against Hepatocellular Carcinoma.
The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment.
The metabolic addiction of cancer stem cells.

Int J Mol Sci. 2022 Aug 06. pii: 8761. [Epub ahead of print]23(15):

Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway.

Gyeongmi Kim, Se-Kyeong Jang, Yu Jin Kim, Hyeon-Ok Jin, Seunghee Bae, Jungil Hong, In-Chul Park, Jae Ho Lee.

  Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.

Keywords:  ASCT2; S6K; chemoresistance; glutamine uptake; mTORC1; metabolic reprogramming; ovarian cancer

DOI:  https://doi.org/10.3390/ijms23158761
J Nutr Biochem. 2022 Aug 04. pii: S0955-2863(22)00184-X. [Epub ahead of print] 109116

1α,25-dihydroxyvitamin D reduction of MCF10A-ras cell viability in extracellular matrix detached conditions is dependent on regulation of pyruvate carboxylase.

Madeline P Sheeley, Violet A Kiesel, Chaylen Andolino, Nadia A Lanman, Shawn S Donkin, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.

  An emerging hallmark of cancer is cellular metabolic reprogramming to adapt to varying cellular environments. Throughout the process of metastasis cancer cells gain anchorage independence which confers survival characteristics when detached from the extracellular matrix (ECM). Previous work demonstrates that the bioactive metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D), suppresses cancer progression, potentially by suppressing the ability of cells to metabolically adapt to varying cellular environments such as ECM detachment. The purpose of the present study was to determine the mechanistic bases of the effects of 1,25(OH)2D on cell survival in ECM-detached conditions. Pretreatment of MCF10A-ras breast cancer cells for three days with 1,25(OH)2D reduced the viability of cells in subsequent detached conditions by 11%. Enrichment of 13C5-glutamine was reduced in glutamate (21%), malate (30%), and aspartate (23%) in detached compared to attached MCF10A-ras cells. Pretreatment with 1,25(OH)2D further reduced glutamine flux into downstream metabolites glutamate (5%), malate (6%), and aspartate (10%) compared to detached vehicle treated cells. Compared to attached cells, detachment increased pyruvate carboxylase (PC) mRNA abundance and protein expression by 95% and 190%, respectively. Consistent with these results, 13C6-glucose derived M+3 labelling was shown to preferentially replenish malate and aspartate, but not citrate pools, demonstrating increased PC activity in detached cells. In contrast, 1,25(OH)2D pretreatment of detached cells reduced PC mRNA abundance and protein expression by 63% and 56%, respectively, and reduced PC activity as determined by decreased 13C6-glucose derived M+3 labeling in citrate (8%) and aspartate (50%) pools, relative to vehicle-treated detached cells. While depletion of PC with doxycycline-inducible shRNA reduced detached cell viability, PC knockdown in combination with 1,25(OH)2D treatment did not additionally affect the viability of detached cells. Further, PC overexpression improved detached cell viability, and inhibited the effect of 1,25(OH)2D on detached cell survival, suggesting that 1,25(OH)2D mediates its effects in detachment through regulation of PC expression. These results suggest that inhibition of PC by 1,25(OH)2D suppresses cancer cell anchorage independence.

Keywords:  1 25-dihydroxyvitamin D; breast cancer; energy metabolism; glucose metabolism; glutamine metabolism; pyruvate carboxylase

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109116
Nat Commun. 2022 Aug 09. 13(1): 4674

MYC sensitises cells to apoptosis by driving energetic demand.

Joy Edwards-Hicks, Huizhong Su, Maurizio Mangolini, Kubra K Yoneten, Jimi Wills, Giovanny Rodriguez-Blanco, Christine Young, Kevin Cho, Heather Barker, Morwenna Muir, Ania Naila Guerrieri, Xue-Feng Li, Rachel White, Piotr Manasterski, Elena Mandrou, Karen Wills, Jingyu Chen, Emily Abraham, Kianoosh Sateri, Bin-Zhi Qian, Peter Bankhead, Mark Arends, Noor Gammoh, Alex von Kriegsheim, Gary J Patti, Andrew H Sims, Juan Carlos Acosta, Valerie Brunton, Kamil R Kranc, Maria Christophorou, Erika L Pearce, Ingo Ringshausen, Andrew J Finch.

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

DOI: https://doi.org/10.1038/s41467-022-32368-z
Front Pharmacol. 2022 ;13 935536

Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.

Chen Chen, Zehua Wang, Yanru Qin.

  Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the DNA, histone, and RNA level, which can alter chromatin state. For almost a century, our focus in cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic enzymes to carry out post-translational modifications of DNA and histone. Genetic mutations in metabolic enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic enzymes leading to tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking cancer metabolism, epigenetics and immunity, and seek optimal immunotherapy-based combinations.

Keywords:  cancer metabolism; epigenetics; immunity; novel anti-cancer strategy; oncology

DOI:  https://doi.org/10.3389/fphar.2022.935536
Molecules. 2022 Aug 08. pii: 5042. [Epub ahead of print]27(15):

Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression.

Shams Tabrez, Torki A Zughaibi, Mehboob Hoque, Mohd Suhail, Mohammad Imran Khan, Azhar U Khan.

  Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.

Keywords:  cancer; glutaminase; glutamine; natural compounds

DOI:  https://doi.org/10.3390/molecules27155042
Yeast. 2022 Aug 08.

Glutamine transport as a possible regulator of nitrogen catabolite repression in Saccharomyces cerevisiae.

Georis Isabelle, Fayyad-Kazan Mohammad, Zaremba Evi, Vierendeels Fabienne, Roovers Martine, Dubois Evelyne.

  Nitrogen Catabolite Repression (NCR) is a major transcriptional control pathway governing nitrogen use in yeast, with several hundred of target genes identified to date. Early and extensive studies on NCR led to the identification of the 4 GATA zinc finger transcription factors, but the primary mechanism initiating NCR is still unclear up till now. To identify novel players of NCR, we have undertaken a genetic screen in an NCR-relieved gdh1Δ mutant, which led to the identification of four genes directly linked to protein ubiquitylation. Ubiquitylation is an important way of regulating amino acid transporters and our observations being specifically observed in glutamine-containing media, we hypothesized that glutamine transport could be involved in establishing NCR. Stabilization of Gap1 at the plasma membrane restored NCR in gdh1Δ cells and AGP1 (but not GAP1) deletion could relieve repression in the ubiquitylation mutants isolated during the screen. Altogether, our results suggest that deregulated glutamine transporter function in all three weak nitrogen derepressed (wnd) mutants restores the repression of NCR-sensitive genes consecutive to GDH1 deletion. This article is protected by copyright. All rights reserved.

Keywords:  Yeast; glutamine; nitrogen catabolite repression; transport; ubiquitylation

DOI:  https://doi.org/10.1002/yea.3809
Redox Biol. 2022 Jul 31. pii: S2213-2317(22)00180-X. [Epub ahead of print]55 102408

Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing.

Lucas B Pontel, Alberto Bueno-Costa, Agustín E Morellato, Juliana Carvalho Santos, Gaël Roué, Manel Esteller.

  Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T- and B- acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.

Keywords:  Acute lymphoblastic leukemia; DNA Methylation; FSP1; Ferroptosis; GPX4; Glutathione

DOI:  https://doi.org/10.1016/j.redox.2022.102408
Cell Discov. 2022 Aug 09. 8(1): 77

GFAT1-linked TAB1 glutamylation sustains p38 MAPK activation and promotes lung cancer cell survival under glucose starvation.

Shupei Wei, Qin Zhao, Ke Zheng, Peiying Liu, Nannan Sha, Yingzi Li, Chunmin Ma, Jingjie Li, Lingang Zhuo, Guanxin Liu, Wenhua Liang, Yuhui Jiang, Tao Chen, Nanshan Zhong.

Reprogrammed cell metabolism is deemed as one of the hallmarks of cancer. Hexosamine biosynthesis pathway (HBP) acts as an "energy sensor" in cells to regulate metabolic fluxes. Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the rate-limiting enzyme of HBP, is broadly found with elevated expression in human cancers though its exact and concrete role in tumorigenesis still remains unknown and needs further investigation. P38 mitogen-activated protein kinase (MAPK) is an important component of stress-signaling pathway and plays a critical role in cell fate decision, whereas the underlying mechanism of its activation under nutrient stress also remains elusive. In this study, we show that glucose deprivation induces the interaction of GFAT1 with transforming growth factor β-activated kinase 1 binding protein 1 (TAB1) in a TAB1 S438 phosphorylation-dependent manner. Subsequently, the binding of GFAT1 to TAB1 facilitates TTLL5-GFAT1-TAB1 complex formation, and the metabolic activity of GFAT1 for glutamate production further contributes to TTLL5-mediated TAB1 glutamylation. In consequence, TAB1 glutamylation promotes the recruitment of p38α MAPK and thus drives p38 MAPK activation. Physiologically, GFAT1-TAB1-p38 signaling promotes autophagy occurrence and thus protects tumor cell survival under glucose deficiency. Clinical analysis indicates that both GFAT1 and TAB1 S438 phosphorylation levels correlate with the poor prognosis of lung adenocarcinoma patients. These findings altogether uncover an unidentified mechanism underlying p38 MAPK signaling regulation by metabolic enzyme upon nutrient stress and provide theoretical rationality of targeting GFAT1 for cancer treatment.

DOI: https://doi.org/10.1038/s41421-022-00423-0
FEBS Lett. 2022 Aug 02.

The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT-20 cells in vitro.

Max Holzknecht, Lena Guerrero-Navarro, Michele Petit, Eva Albertini, Elisabeth Damisch, Anna Simonini, Fernando Schmitt, Walther Parson, Heidelinde Fiegl, Alexander Weiss, Pidder Jansen-Duerr.

  The mitochondrial enzyme fumarylacetoacetate hydrolase domain-containing protein 1 (FAHD1) was identified to be upregulated in breast cancer tissues. Here, we show that FAHD1 is indispensable for the survival of BT-20 cells, representing the basal breast cancer cell type. A lentiviral knock-down of FAHD1 in the breast cancer cell lines MCF-7 and BT-20 results in lower succinate dehydrogenase (complex II) activity. In luminal MCF-7 cells, this leads to reduced proliferation when cultured in medium containing only glutamine as the carbon source. Of note, both cell lines show attenuated protein levels of the enzyme glutaminase (GLS) which activates programmed cell death in BT-20. These findings demonstrate that FAHD1 is crucial for the functionality of complex II in breast cancer cells and acts on glutaminolysis in the mitochondria.

Keywords:  FAHD1; MCF-7; TNBC; glutaminase; oxaloacetate; succinate dehydrogenase

DOI:  https://doi.org/10.1002/1873-3468.14462
World J Gastrointest Oncol. 2022 Jun 15. 14(6): 1124-1140

Glutamine deprivation impairs function of infiltrating CD8+ T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis.

Wei Wang, Meng-Nan Guo, Ning Li, De-Quan Pang, Jing-Hua Wu.

  BACKGROUND: The functions of infiltrating CD8+ T cells are often impaired due to tumor cells causing nutrient deprivation in the tumor microenvironment. Thus, the mechanisms of CD8+ T cell dysfunction have become a hot research topic, and there is increased interest on how changes in metabolomics correlate with CD8+ T cell dysfunction.AIM: To investigate whether and how glutamine metabolism affects the function of infiltrating CD8+ T cells in hepatocellular carcinoma.
METHODS: Immunohistochemical staining and immunofluorescence were performed on surgically resected liver tissues from patients. Differentially expressed genes in infiltrating CD8+ T cells in hepatocellular carcinoma were detected using RNA sequencing. Activated CD8+ T cells were co-cultured with Huh-7 cells for 3 d. The function and mitochondrial status of CD8+ T cells were analyzed by flow cytometry, quantitative real-time polymerase chain reaction, and transmission electron microscopy. Next, CD8+ T cells were treated with the mitochondrial protective and damaging agents. Functional alterations in CD8+ T cells were detected by flow cytometry. Then, complete medium without glutamine was used to culture cells and their functional changes and mitochondrial status were detected.
RESULTS: There were a large number of infiltrating PD-1+CD8+ T cells in liver cancer tissues. Next, we co-cultured CD8+ T cells and Huh-7 cells to explore the regulatory effect of hepatoma cells on CD8+ T cells. Flow cytometry results revealed increased PD-1 expression and decreased secretion of perforin (PRF1) and granzyme B (GZMB) by CD8+ T cells in the co-culture group. Meanwhile, JC-1 staining was decreased and the levels of reactive oxygen species and apoptosis were increased in CD8+ T cells of the co-culture group; additionally, the mitochondria of these cells were swollen. When CD8+ T cells were treated with the mitochondrial protective and damaging agents, their function was restored and inhibited, respectively, through the mitochondrial damage and apoptotic pathways. Subsequently, complete medium without glutamine was used to culture cells. As expected, CD8+ T cells showed functional downregulation, mitochondrial damage, and apoptosis.
CONCLUSION: Glutamine deprivation impairs the function of infiltrating CD8+ T cells in hepatocellular carcinoma through the mitochondrial damage and apoptotic pathways.

Keywords:  CD8+ T cells; Glutamine; Hepatocellular carcinoma; Mitochondrial damage; T cell function

DOI:  https://doi.org/10.4251/wjgo.v14.i6.1124
Front Cell Dev Biol. 2022 ;10 859236

Computational Metabolomics Reveals the Potential Mechanism of Matrine Mediated Metabolic Network Against Hepatocellular Carcinoma.

Kexin Wang, Xiangmin Ye, Chuanhui Yin, Qing Ren, Yupeng Chen, Xuemei Qin, Chuanzhi Duan, Aiping Lu, Li Gao, Daogang Guan.

  Hepatocellular carcinoma (HCC) is a complex issue in cancer treatment in the world at present. Matrine is the main active ingredient isolated from Sophora flavescens air and possesses excellent antitumor effects in HCC. However, the specific underlying mechanisms, especially the possible relationships between the anti-HCC effect of matrine and the related metabolic network of HCC, are not yet clear and need further clarification. In this study, an integrative metabolomic-based bioinformatics algorithm was designed to explore the underlying mechanism of matrine on HCC by regulating the metabolic network. Cell clone formation, invasion, and adhesion assay were utilized in HCC cells to evaluate the anti-HCC effect of matrine. A cell metabolomics approach based on LC-MS was used to obtain the differential metabolites and metabolic pathways regulated by matrine. The maximum activity contribution score model was developed and applied to calculate high contribution target genes of matrine, which could regulate a metabolic network based on the coexpression matrix of matrine-regulated metabolic genes and targets. Matrine significantly repressed the clone formation and invasion, enhanced cell-cell adhesion, and hampered cell matrix adhesion in SMMC-7721 cells. Metabolomics results suggested that matrine markedly regulated the abnormal metabolic network of HCC by regulating the level of choline, creatine, valine, spermidine, 4-oxoproline, D-(+)-maltose, L-(-)-methionine, L-phenylalanine, L-pyroglutamic acid, and pyridoxine, which are involved in D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, etc. Our proposed metabolomic-based bioinformatics algorithm showed that the regulating metabolic networks of matrine exhibit anti-HCC effects through acting on MMP7, ABCC1, PTGS1, etc. At last, MMP7 and its related target β-catenin were validated. Together, the metabolomic-based bioinformatics algorithm reveals the effects of the regulating metabolic networks of matrine in treating HCC relying on the unique characteristics of the multitargets and multipathways of traditional Chinese medicine.

Keywords:  Hepatocellular carcinoma; MACS model; computational metabolomics; matrine; mechanism; metabolic network

DOI:  https://doi.org/10.3389/fcell.2022.859236
Cancers (Basel). 2022 Jul 27. pii: 3661. [Epub ahead of print]14(15):

The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment.

Domenica Berardi, Yasmin Hunter, Lisa van den Driest, Gillian Farrell, Nicholas J W Rattray, Zahra Rattray.

  Metabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely to fingerprint the impact of olaparib treatment in cellular metabolism. Here, we report the biomolecular response of breast cancer cell lines with DNA damage repair defects to olaparib exposure. Following evaluation of olaparib sensitivity in breast cancer cell lines, we immunoprobed DNA double strand break foci and evaluated changes in cellular metabolism at various olaparib treatment doses using untargeted mass spectrometry-based metabolomics analysis. Following identification of altered features, we performed pathway enrichment analysis to measure key metabolic changes occurring in response to olaparib treatment. We show a cell-line-dependent response to olaparib exposure, and an increased susceptibility to DNA damage foci accumulation in triple-negative breast cancer cell lines. Metabolic changes in response to olaparib treatment were cell-line and dose-dependent, where we predominantly observed metabolic reprogramming of glutamine-derived amino acids and lipids metabolism. Our work demonstrates the effectiveness of combining molecular biology and metabolomics studies for the comprehensive characterisation of cell lines with different genetic profiles. Follow-on studies are needed to map the baseline metabolism of breast cancer cells and their unique response to drug treatment. Fused with genomic and transcriptomics data, such readout can be used to identify key oncometabolites and inform the rationale for the design of novel drugs or chemotherapy combinations.

Keywords:  DNA damage; breast cancer; metabolic reprogramming; oncometabolites; precision medicine; triple-negative

DOI:  https://doi.org/10.3390/cancers14153661
Front Oncol. 2022 ;12 955892

The metabolic addiction of cancer stem cells.

Om Saswat Sahoo, Karthikeyan Pethusamy, Tryambak P Srivastava, Joyeeta Talukdar, Mohammed S Alqahtani, Mohamed Abbas, Ruby Dhar, Subhradip Karmakar.

  Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.

Keywords:  cancer stem cells; cross talks; epigenetics; metabolism; oncometabolites

DOI:  https://doi.org/10.3389/fonc.2022.955892