Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway

Payen, Valéry L.; Porporato, Paolo E.; Baselet, Bjorn; Sonveaux, Pierre

doi:10.1007/s00018-015-2098-5

Cited by 188 publications

(169 citation statements)

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“…Many studies reveal that the execution of aggressive tumor agenda required a specific rewiring of the metabolic flux. The relationship between the glycolysis and metastasis in cancers has been increasingly acknowledged [27]. By targeting one of the most important glycolytic rate-limiting enzymes, PFKFB3, using its selective inhibitor PFK15, we proved that the blockage of glycolysis in HNSCC cells not only halted tumor growth by inhibiting cell proliferation but also alleviated cancer metastasis by suppressing the formation of protrusions.…”

Section: Discussionmentioning

confidence: 93%

Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma

Yang

Liu

et al. 2017

J Exp Clin Cancer Res

114

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BackgroundMany cancers including head and neck squamous cell carcinoma (HNSCC) are characterized by a metabolic rewiring with increased glucose uptake and lactate production, termed as aerobic glycolysis. Targeting aerobic glycolysis presents a promising strategy for cancer therapy. This study investigates the therapeutic potential of glycolysis blockage by targeting phosphofructokinase-2/fructose-2, 6-bisphosphatase 3 (PFKFB3) in HNSCC.Methods1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) was used as a selective antagonist of PFKFB3. Glycolytic flux was determined by measuring glucose uptake, lactate production and ATP yield. PFKFB3 expression was examined using HNSCC tissue arrays. Cell proliferation, apoptosis and motility were analysed. HNSCC xenograft mouse model and metastasis mouse model were established to examine the therapeutic efficacy of PFK15 in vivo.ResultsHNSCC showed an increased PFKFB3 expression compared with adjacent mucosal tissues (P < 0.01). Targeting PFKFB3 via PFK15 significantly reduced the glucose uptake, lactate production and ATP generation in HNSCC cell lines. PFK15 suppressed cell proliferation, halted cell cycle progression and induced cell apoptosis. The invadopodia of HNSCC cells was markedly reduced after PFK15 treatment, thereby impairing cell motility and extracellular matrix degradation ability. The in vivo data from the xenograft mice models proved that PFK15 administration suppressed the tumor growth. And the results from the metastatic mice models showed administration of PFK15 alleviated the lung metastasis of HNSCC and extended the life expectancy of mice.ConclusionsThe pharmacological inhibition of PFKFB3 via PFK15 suppressed tumor growth and alleviated metastasis in HNSCC, offering a promising strategy for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0481-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 93%

Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma

Yang

Liu

et al. 2017

J Exp Clin Cancer Res

114

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“…A typ i cal meta bolic al ter ation well es tab lished to pro mote metas ta sis is aci do sis in the pri mary tu mor [146]. In many pa tients, an in verted pH gra di ent across the plasma mem brane of can cer cells has been ob served com pared to cor re spond ing healthy tis sues.…”

Section: Metabolic Contribution To Cancer Metastasismentioning

confidence: 99%

“…Di vert ing glu cose from gly col y sis to the PPP could there fore help the cells to re sist to de tach ment in duced ox ida tive stress [9]. As a main con trib u tor to ex tra cel lu lar acid i fi ca tion and lac tate pro duc tion and be cause of its con nec tion with the PPP, an in creased gly colytic flux has been as so ci ated with can cer metas ta sis [146]. How ever, ox ida tive mi to chon dr ial me tab o lism is cur rently emerg ing as an other ma jor reg u la tor of tu mor metas ta sis.…”

Section: Metabolic Contribution To Cancer Metastasismentioning

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

178

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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“…One of the hallmarks of cancer metabolism is enhanced glucose uptake and its conversion to lactate despite the presence of available oxygen (i.e., the Warburg effect or aerobic glycolysis) (14). This process not only results in the rapid generation of ATP for cellular energetics through glycolysis, but can also contribute to biosynthetic pathways required for proliferation (15,16). Fluorodeoxyglucose (FDG) PET is a well-established tool for quantifying glucose uptake in tumors.…”

Section: Introductionmentioning

confidence: 99%