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      Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours

      review-article
      Author(s): 1 , 1 , , , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: Mitochondria, Cancer, Metabolism, Calcium, ROS, Abbreviations: 2-DG, 2-deoxyglucose, 18F-FDG, 2-[18F]fluoro-2-deoxy-d-glucose, α-KG, alpha-ketoglutarate, α-KGDH, alpha-ketoglutarate dehydrogenase, AGEs, advanced glycation products, AML, acute myeloid leukemia, AMPK, AMP-activated protein kinase, ASS1, argininosuccinate synthase 1, ATP, adenosine triphosphate, BAP1, BRCA1-associated protein 1, Ca2+, calcium ion, CQ, chloroquine, D-2-HG, D-2-hydroxyglutarate, DCA, dichloroacetate, EGFR, epidermal growth factor receptor, EMT, epithelial-to-mesenchymal transition, ER, endoplasmic reticulum, ETC, electron transport chain, FAD, flavin adenine dinucleotide, FH, fumarate hydratase, GLS, glutaminase, HIF-1, hypoxia-inducible factor-1, HSP90, heat shock protein 90, IDH, isocitrate dehydrogenase, IP3R3, inositol 1,4,5-trisphosphate receptor 3, KDMs, JmjC domain-containing demethylases, KEAP1, kelch-like ECH-associated protein 1, LDHA, lactate dehydrogenase A, LOF, loss-of-function, MAMs, mitochondria associated membranes, MCU, mitochondrial calcium uniporter, MCUR1, mitochondrial Ca2+ regulator 1, MEF2, myocyte enhancer factor 2, MICU1, mitochondrial calcium uptake 1, mPTP, mitochondrial permeability transition pore, MPT, mitochondrial permeability transition, mROS, mitochondrial ROS, mtDNA, mitochondrial DNA, mTOR, mammalian target of rapamycin, NADPH, nicotinamide adenine dinucleotide phosphate, Nf-kb, nuclear factor kappa-light-chain-enhancer of activated B cells, Nrf2, nuclear factor (erythroid-derived 2) factor 2, NSAIDs, nonsteroidal anti-inflammatory drugs, OCR, oxygen consumption rate, OXPHOS, oxidative phosphorylation, PC, prostate cancer, PDC, pyruvate dehydrogenase complex, PDH, pyruvate dehydrogenase, PDKs, pyruvate dehydrogenase kinase, PDT, photodynamic therapy, PHD, prolyl hydroxylase, PET, positron emission tomography, PI3K, phosphatidylinositol 3-kinase, PML, promyelocytic leukaemia protein, PTEN, phosphatase and tensin homologue, PTK2B, protein tyrosine kinase 2 beta, ROS, reactive oxygen species, SDH, succinate dehydrogenase, TCA, tricarboxylic acid, TFBM2, mitochondrial transcription factor B2, TRAP-1, TNF receptor associated protein, VK3, vitamin K3

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          Abstract

          Mitochondria are dynamic organelles that have essential metabolic activity and are regarded as signalling hubs with biosynthetic, bioenergetics and signalling functions that orchestrate key biological pathways. However, mitochondria can influence all processes linked to oncogenesis, starting from malignant transformation to metastatic dissemination. In this review, we describe how alterations in the mitochondrial metabolic status contribute to the acquisition of typical malignant traits, discussing the most recent discoveries and the many unanswered questions. We also highlight that expanding our understanding of mitochondrial regulation and function mechanisms in the context of cancer cell metabolism could be an important task in biomedical research, thus offering the possibility of targeting mitochondria for the treatment of cancer.

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          Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

          William Wheaton, Samuel Weinberg, Robert B. Hamanaka … (2014)
          Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I. DOI: http://dx.doi.org/10.7554/eLife.02242.001
          Article 0 comments Cited 459 times – based on 0 reviews     Review now
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            Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells

            Anne Le, Andrew N. Lane, Max Hamaker … (2012)
            Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy. Copyright © 2012 Elsevier Inc. All rights reserved.
            Article 0 comments Cited 425 times – based on 0 reviews     Review now
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              Regulation of autophagy by cytoplasmic p53.

              Ezgi Tasdemir, M Chiara Maiuri, Lorenzo Galluzzi … (2008)
              Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
              Article 0 comments Cited 352 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Carlotta Giorgi
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 17 August 2020
                Publication date Collection: September 2020
                Publication date (Electronic): 17 August 2020
                Volume: 59
                Electronic Location Identifier: 102943
                Affiliations
                [0001]Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
                Author notes
                [* ]Correspondence to: Carlotta Giorgi, Department of Medical Sciences, University of Ferrara, Italy. grgclt@ 123456unife.it
                [1]

                Both the authors contributed equally to this work

                Article
                Publisher ID: S2352-3964(20)30319-4 Publisher ID: 102943
                DOI: 10.1016/j.ebiom.2020.102943
                PMC ID: 7452656
                PubMed ID: 32818805
                SO-VID: 90b79b9c-a0d8-459f-94ff-ffc0a2268223
                Copyright © © 2020 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 3 June 2020
                Date revision received : 22 July 2020
                Date accepted : 22 July 2020
                Categories
                Subject: Review

                Keywords: mitochondria,cancer,metabolism,calcium,ros,abbreviations: 2-dg, 2-deoxyglucose,18f-fdg, 2-[18f]fluoro-2-deoxy-d-glucose,α-kg, alpha-ketoglutarate,α-kgdh, alpha-ketoglutarate dehydrogenase,ages, advanced glycation products,aml, acute myeloid leukemia,ampk, amp-activated protein kinase,ass1, argininosuccinate synthase 1,atp, adenosine triphosphate,bap1, brca1-associated protein 1,ca2+, calcium ion,cq, chloroquine,d-2-hg, d-2-hydroxyglutarate,dca, dichloroacetate,egfr, epidermal growth factor receptor,emt, epithelial-to-mesenchymal transition,er, endoplasmic reticulum,etc, electron transport chain,fad, flavin adenine dinucleotide,fh, fumarate hydratase,gls, glutaminase,hif-1, hypoxia-inducible factor-1,hsp90, heat shock protein 90,idh, isocitrate dehydrogenase,ip3r3, inositol 1,4,5-trisphosphate receptor 3,kdms, jmjc domain-containing demethylases,keap1, kelch-like ech-associated protein 1,ldha, lactate dehydrogenase a,lof, loss-of-function,mams, mitochondria associated membranes,mcu, mitochondrial calcium uniporter,mcur1, mitochondrial ca2+ regulator 1,mef2, myocyte enhancer factor 2,micu1, mitochondrial calcium uptake 1,mptp, mitochondrial permeability transition pore,mpt, mitochondrial permeability transition,mros, mitochondrial ros,mtdna, mitochondrial dna,mtor, mammalian target of rapamycin,nadph, nicotinamide adenine dinucleotide phosphate,nf-kb, nuclear factor kappa-light-chain-enhancer of activated b cells,nrf2, nuclear factor (erythroid-derived 2) factor 2,nsaids, nonsteroidal anti-inflammatory drugs,ocr, oxygen consumption rate,oxphos, oxidative phosphorylation,pc, prostate cancer,pdc, pyruvate dehydrogenase complex,pdh, pyruvate dehydrogenase,pdks, pyruvate dehydrogenase kinase,pdt, photodynamic therapy,phd, prolyl hydroxylase,pet, positron emission tomography,pi3k, phosphatidylinositol 3-kinase,pml, promyelocytic leukaemia protein,pten, phosphatase and tensin homologue,ptk2b, protein tyrosine kinase 2 beta,ros, reactive oxygen species,sdh, succinate dehydrogenase,tca, tricarboxylic acid,tfbm2, mitochondrial transcription factor b2,trap-1, tnf receptor associated protein,vk3, vitamin k3
                Data availability:
                Keywords: mitochondria, cancer, metabolism, calcium, ros, abbreviations: 2-dg, 2-deoxyglucose, 18f-fdg, 2-[18f]fluoro-2-deoxy-d-glucose, α-kg, alpha-ketoglutarate, α-kgdh, alpha-ketoglutarate dehydrogenase, ages, advanced glycation products, aml, acute myeloid leukemia, ampk, amp-activated protein kinase, ass1, argininosuccinate synthase 1, atp, adenosine triphosphate, bap1, brca1-associated protein 1, ca2+, calcium ion, cq, chloroquine, d-2-hg, d-2-hydroxyglutarate, dca, dichloroacetate, egfr, epidermal growth factor receptor, emt, epithelial-to-mesenchymal transition, er, endoplasmic reticulum, etc, electron transport chain, fad, flavin adenine dinucleotide, fh, fumarate hydratase, gls, glutaminase, hif-1, hypoxia-inducible factor-1, hsp90, heat shock protein 90, idh, isocitrate dehydrogenase, ip3r3, inositol 1,4,5-trisphosphate receptor 3, kdms, jmjc domain-containing demethylases, keap1, kelch-like ech-associated protein 1, ldha, lactate dehydrogenase a, lof, loss-of-function, mams, mitochondria associated membranes, mcu, mitochondrial calcium uniporter, mcur1, mitochondrial ca2+ regulator 1, mef2, myocyte enhancer factor 2, micu1, mitochondrial calcium uptake 1, mptp, mitochondrial permeability transition pore, mpt, mitochondrial permeability transition, mros, mitochondrial ros, mtdna, mitochondrial dna, mtor, mammalian target of rapamycin, nadph, nicotinamide adenine dinucleotide phosphate, nf-kb, nuclear factor kappa-light-chain-enhancer of activated b cells, nrf2, nuclear factor (erythroid-derived 2) factor 2, nsaids, nonsteroidal anti-inflammatory drugs, ocr, oxygen consumption rate, oxphos, oxidative phosphorylation, pc, prostate cancer, pdc, pyruvate dehydrogenase complex, pdh, pyruvate dehydrogenase, pdks, pyruvate dehydrogenase kinase, pdt, photodynamic therapy, phd, prolyl hydroxylase, pet, positron emission tomography, pi3k, phosphatidylinositol 3-kinase, pml, promyelocytic leukaemia protein, pten, phosphatase and tensin homologue, ptk2b, protein tyrosine kinase 2 beta, ros, reactive oxygen species, sdh, succinate dehydrogenase, tca, tricarboxylic acid, tfbm2, mitochondrial transcription factor b2, trap-1, tnf receptor associated protein, vk3, vitamin k3

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