Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation

Preter, Géraldine De; Neveu, Marie‐Aline; Danhier, Pierre; Brisson, Lucie; Payen, Valéry L.; Porporato, Paolo E.; Jordan, Bénédicte F.; Sonveaux, Pierre; Gallez, Bernard

doi:10.18632/oncotarget.6272

Cited by 63 publications

(48 citation statements)

References 38 publications

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“…Al though stud ies on cell cul tures showed that mi to chon dr ial res pi ra tion is lim ited in sev eral can cer cell lines [262][263][264], in vivo data showed that mi to chon dr ial oxy gen con sump tion is not im paired in tu mors and that ox ida tive glu cose me tab o lism is re quired for tu mor growth [265]. The dis crep ancy be tween in vitro and in vivo ob ser va tions pleads for the use of spon ta neously aris ing tu mor mod els, which in te grate dri ver mu ta tions, the tu mor mi croen vi ron ment and the sur round ing 3D tis sue ar chi tec ture [253,266,267].…”

Section: Metabolic Differences Between In Vitro and In Vivo Models Ofmentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

Self Cite

177

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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Section: Metabolic Differences Between In Vitro and In Vivo Models Ofmentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

Self Cite

177

139

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show abstract

“…For example, in combination with certain platinum-based chemotherapies, DCA has been shown to enhance cytotoxicity in several solid tumor derived cell lines [61,62] and to reverse cisplatin resistance [63]. It is possible that DCA exacerbates the effects of these DNA cross-linking agents by reducing the biosynthesis of nucleotides necessary for DNA repair [64] or through other as-yet-undetermined metabolic effects.…”

Section: Catching Cancer In the Metabolic Crab Pot: Attempts Failurementioning

confidence: 99%

Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

Olson

Schell

Rutter

2016

Trends in Biochemical Sciences

113

100

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Dysregulated metabolism is an emerging hallmark of cancer and there is abundant interest in developing therapies to selectively target these aberrant metabolic phenotypes. Sitting at the decision point between mitochondrial carbohydrate oxidation and aerobic glycolysis (i.e., the “Warburg Effect”), the synthesis and consumption of pyruvate is tightly controlled and is often differentially regulated in cancer cells. This review examines recent efforts toward understanding and targeting mitochondrial pyruvate metabolism, and addresses some of the successes, pitfalls and significant challenges of metabolic therapy to date.

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“…Otto Warburg identified in the 1920s the presence of a faster glycolytic flux in tumor cells [4], characterized by a high glucose uptake and increased lactate production even in the presence of oxygen. Despite a limited capacity for ATP production, aerobic glycolysis confers a major advantage to tumor cells by supporting proliferation and biomass production [3], [5], [6]. During decades, the loss of coupling between glycolysis and oxidative phosphorylation (OXPHOS) in tumor cells has been assigned to major mitochondrial dysfunctions [7].…”

Section: Introductionmentioning

confidence: 99%

Multimodality Imaging Identifies Distinct Metabolic Profiles In Vitro and In Vivo

et al. 2016

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The study of alterations of tumor metabolism should allow the identification of new targets for innovative anticancer strategies. Metabolic alterations are generally established in vitro, and conclusions are often extrapolated to the in vivo situation without further tumor metabolic phenotyping. To highlight the key role of microenvironment on tumor metabolism, we studied the response of glycolytic and oxidative tumor models to metabolic modulations in vitro and in vivo. MDA-MB-231 and SiHa tumor models, characterized in vitro as glycolytic and oxidative, respectively, were studied. Theoretically, when passing from a hypoxic state to an oxygenated state, a Warburg phenotype should conserve a glycolytic metabolism, whereas an oxidative phenotype should switch from glycolytic to oxidative metabolism (Pasteur effect). This challenge was applied in vitro and in vivo to evaluate the impact of different oxic conditions on glucose metabolism. 18F-fluorodeoxyglucose uptake, lactate production, tumor oxygenation, and metabolic fluxes were monitored in vivo using positron emission tomography, microdialysis, electron paramagnetic resonance imaging, and 13C-hyperpolarizated magnetic resonance spectroscopy, respectively. In vitro, MDA-MB-231 cells were glycolytic under both hypoxic and oxygenated conditions, whereas SiHa cells underwent a metabolic shift after reoxygenation. On the contrary, in vivo, the increase in tumor oxygenation (induced by carbogen challenge) led to a similar metabolic shift in glucose metabolism in both tumor models. The major discordance in metabolic patterns observed in vitro and in vivo highlights that any extrapolation of in vitro metabolic profiling to the in vivo situation should be taken cautiously and that metabolic phenotyping using molecular imaging is mandatory in vivo.

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Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation

Cited by 63 publications

References 38 publications

Cancer metabolism in space and time: Beyond the Warburg effect

Cancer metabolism in space and time: Beyond the Warburg effect

Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

Multimodality Imaging Identifies Distinct Metabolic Profiles In Vitro and In Vivo

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