Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

Mathupala, Saroj P.; Ko, Young Hee; Pedersen, Peter L.

doi:10.1038/sj.onc.1209603

Cited by 689 publications

(648 citation statements)

References 91 publications

(87 reference statements)

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“…The binding to mitochondria also undergoes feedback inhibition by G-6P. 9,[19][20][21][22] In the last decade, many seminal studies have emphasized the importance of metabolic re-programming in cancer biology. HK-II upregulation has been suggested to be a major contributor to the elevated glycolysis, even in the presence of oxygen, in cancer as first reported by Dr. Otto Warburg 23 in 1930 (Warburg effect).…”

Section: Hexokinase II In Metabolismmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Hexokinase II In Metabolismmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…Compared with the control, let-7d mimic significantly inhibited the expression of luciferase gene with an intact Hk2 3 0 UTR, whereas with a mutated let-7d-binding site, there was unrestrained luciferase expression in the presence of let-7d ( Figure 4F). Although it is known that Hk2-as the rate-limiting enzyme directly activating glucose to be a glycolysis substrate by phosphorylating glucose to glucose 6-phosphate-plays an important role in enhancing glycolysis in cancer cells (Mathupala et al, 2006), the functional role of Hk2 in B cells has not previously been addressed. To further test whether targeting hk2 is one of the mechanisms that was involved in let-7adf-mediated IgM production and glucose uptake, the HK2 transcript was overexpressed in let7adf iTg B cells, and we found that it rescued the effect of let-7adf overexpression on IgM production and glucose uptake ( Figures 4G and 4H).…”

Section: Comprehensive Repression Of All Let-7 Mirnas Enhances Igm Prmentioning

confidence: 99%

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

et al. 2018

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“…The re lease of mi to chon dr ial Ca is crit i cally in volved in the ini ti a tion and ef fec tu a tion of apop totic cell death. In this con text, AKT ac ti va tion con fers re sis tance to apop to sis by stim u lat ing Bcl 2 pro tein ex pres sion [124] and the bind ing of HK2 to VDAC on the mi to chon dr ial sur face [125].…”

Section: Metabolic Regulation Of Cancer Cell Deathmentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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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Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

Cited by 689 publications

References 91 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

Cancer metabolism in space and time: Beyond the Warburg effect

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