BACKGROUND: Hexokinases (HKs) are well-studied enzymes catalyzing the first step of glycolysis. However, non-canonical regulatory roles of HKs are still incompletely understood. Here, we hypothesized that HKs comprise one of the missing links between high-dose metformin and the inhibition of the respiratory chain in cancer. METHODS: We tested the isoenzyme-specific regulatory roles of HKs in ovarian cancer cells by examining the effects of the deletions of HK1 and HK2 in TOV-112D ovarian adenocarcinoma cells. We reverted these effects by re-introducing wild-type HK1 and HK2, and we compared the HK1 revertant with the knock-in of catalytically dead HK1 p.D656A. We subjected these cells to a battery of metabolic and proliferation assays and targeted GC×GC-MS metabolomics. RESULTS: We found that the HK1 depletion (but not the HK2 depletion) sensitized ovarian cancer cells to high-dose metformin during glucose starvation. We confirmed that this newly uncovered role of HK1 is glycolysis-independent by the introduction of the catalytically dead HK1. The expression of catalytically dead HK1 stimulated similar changes in levels of TCA intermediates, aspartate and cysteine, and in glutamate as were induced by the HK2 deletion. In contrast, HK1 deletion increased the levels of branched amino acids; this effect was completely eliminated by the expression of catalytically dead HK1. Furthermore, HK1 revertants but not HK2 revertants caused a strong increase of NADPH/NADP ratios independently on the presence of glucose or metformin. The HK1 deletion (but not HK2 deletion) suppressed the growth of xenotransplanted ovarian cancer cells and nearly abolished the tumor growth when the mice were fed the glucose-free diet. CONCLUSIONS: We provided the evidence that HK1 is involved in the so far unknown glycolysis-independent HK1-metformin axis and influences metabolism even in glucose-free conditions.

3rd Faculty of Medicine Charles University Ruská 87 CZ 100 00 Prague Czech Republic

CLIP Childhood Leukaemia Investigation Prague Prague Czech Republic

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University Prague Czech Republic

Faculty of Science BIOCEV Charles University Vestec Czech Republic

University Hospital Kralovské Vinohrady Prague Czech Republic

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492. PubMed DOI

Sundar S, Neal RD, Kehoe S. Diagnosis of ovarian cancer. BMJ. 2015;351:h4443. doi: 10.1136/bmj.h4443. PubMed DOI

Wright AA, Bohlke K, Armstrong DK, Bookman MA, Cliby WA, Coleman RL, Dizon DS, Kash JJ, Meyer LA, Moore KN, Olawaiye AB, Oldham J, Salani R, Sparacio D, Tew WP, Vergote I, Edelson MI. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. Gynecol Oncol. 2016;143(1):3–15. doi: 10.1016/j.ygyno.2016.05.022. PubMed DOI PMC

Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–2505. doi: 10.1056/NEJMoa1810858. PubMed DOI

Gentric G, Kieffer Y, Mieulet V, Goundiam O, Bonneau C, Nemati F, Hurbain I, Raposo G, Popova T, Stern MH, Lallemand-Breitenbach V, Müller S, Cañeque T, Rodriguez R, Vincent-Salomon A, de Thé H, Rossignol R, Mechta-Grigoriou F. PML-regulated mitochondrial metabolism enhances chemosensitivity in human ovarian cancers. Cell Metab. 2019;29(1):156–173. doi: 10.1016/j.cmet.2018.09.002. PubMed DOI PMC

Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell. 2017;168(4):657–669. doi: 10.1016/j.cell.2016.12.039. PubMed DOI PMC

Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–530. doi: 10.1085/jgp.8.6.519. PubMed DOI PMC

Wilson JE. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol. 2003;206(12):2049–2057. doi: 10.1242/jeb.00241. PubMed DOI

John S, Weiss JN, Ribalet B. Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS ONE. 2011;6(3):e17674. doi: 10.1371/journal.pone.0017674. PubMed DOI PMC

Graham NA, Minasyan A, Lomova A, Cass A, Balanis NG, Friedman M, Chan S, Zhao S, Delgado A, Go J, Beck L, Hurtz C, Ng C, Qiao R, ten Hoeve J, Palaskas N, Wu H, Müschen M, Multani AS, Port E, Larson SM, Schultz N, Braas D, Christofk HR, Mellinghoff IK, Graeber TG. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol. 2017;13(2):914. doi: 10.15252/msb.20167159. PubMed DOI PMC

Cheung EC, Ludwig RL, Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci USA. 2012;109(50):20491–20496. doi: 10.1073/pnas.1206530109. PubMed DOI PMC

Martin PL, Yin J-J, Seng V, Casey O, Corey E, Morrissey C, Simpson RM, Kelly K. Androgen deprivation leads to increased carbohydrate metabolism and hexokinase 2-mediated survival in Pten/Tp53-deficient prostate cancer. Oncogene. 2017;36(4):525–533. doi: 10.1038/onc.2016.223. PubMed DOI PMC

Mergenthaler P, Kahl A, Kamitz A, van Laak V, Stohlmann K, Thomsen S, Klawitter H, Przesdzing I, Neeb L, Freyer D, Priller J, Collins TJ, Megow D, Dirnagl U, Andrews DW, Meisel A. Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state. Proc Natl Acad Sci USA. 2012;109(5):1518–1523. doi: 10.1073/pnas.1108225109. PubMed DOI PMC

Roh J-I, Kim Y, Oh J, Kim Y, Lee J, Lee J, Chun KH, Lee HW. Hexokinase 2 is a molecular bridge linking telomerase and autophagy. PLoS ONE. 2018;13(2):e0193182. doi: 10.1371/journal.pone.0193182. PubMed DOI PMC

Amendola CR, Mahaffey JP, Parker SJ, Ahearn IM, Chen WC, Zhou M, Court H, Shi J, Mendoza SL, Morten MJ, Rothenberg E, Gottlieb E, Wadghiri YZ, Possemato R, Hubbard SR, Balmain A, Kimmelman AC, Philips MR. KRAS4 directly regulates HK1. Nature. 2019;576(7787):482–486. doi: 10.1038/s41586-019-1832-9. PubMed DOI PMC

Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res. 2010;3(11):1451–1461. doi: 10.1158/1940-6207.CAPR-10-0157. PubMed DOI

Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61–67. doi: 10.1097/AOG.0b013e3182393ab3. PubMed DOI PMC

Madiraju AK, Erion DM, Rahimi Y, Zhang X-M, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–546. doi: 10.1038/nature13270. PubMed DOI PMC

Shaw RJ, Lamia KA, Vasquez D, Koo S-H, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–1646. doi: 10.1126/science.1120781. PubMed DOI PMC

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signaling by decreasing production of cyclic AMP. Nature. 2013;494(7436):256–260. doi: 10.1038/nature11808. PubMed DOI PMC

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174. doi: 10.1172/JCI13505. PubMed DOI PMC

Furkan Alkan H, Walter KE, Luengo A, Madreiter-Sokolowski CT, Stryeck S, Lau AN, et al. Cytosolic aspartate availability determines cell survival when glutamine is limiting. Cell Metab. 2018;28(5):706–720. doi: 10.1016/j.cmet.2018.07.021. PubMed DOI PMC

He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–162. doi: 10.1016/j.cmet.2015.01.003. PubMed DOI

Andrzejewski S, Gravel SP, Pollak M, St-Pierre J. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab. 2014;2(1):12. doi: 10.1186/2049-3002-2-12. PubMed DOI PMC

Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, Viollet B, DeBerardinis RJ, Jones RG. Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol. 2015;13(12):e1002309. doi: 10.1371/journal.pbio.1002309. PubMed DOI PMC

Shepherd TG, Thériault BL, Campbell EJ, Nachtigal MW. Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients. Nat Protoc. 2006;1(6):2643–2649. doi: 10.1038/nprot.2006.328. PubMed DOI

Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281–2308. doi: 10.1038/nprot.2013.143. PubMed DOI PMC

Labun K, Montague TG, Krause M, Cleuren YNT, Tjeldnes H, Valen E. CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res. 2019;47(W1):W171–W174. doi: 10.1093/nar/gkz365. PubMed DOI PMC

Konermann S. SAM target sgRNA cloning protocol. Available from https://media.addgene.org/cms/filer_public/3e/e1/3ee1ce9c-99f9-4074-9a28-109d34971471/zhang-lab-sam-cloning-protocol.pdf.

Thakore PI, D’Ippolito AM, Song L, Safi A, Shivakumar NK, Kabadi AM, et al. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods. 2015;12(12):1143–1149. doi: 10.1038/nmeth.3630. PubMed DOI PMC

Heckl D, Kowalczyk MS, Yudovich D, Belizaire R, Puram RV, McConkey ME, et al. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat Biotechnol. 2014;32(9):941–946. doi: 10.1038/nbt.2951. PubMed DOI PMC

Yuan M, Breitkopf SB, Yang X, Asara JM. A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat Protocols. 2012;7(5):872–878. doi: 10.1038/nprot.2012.024. PubMed DOI PMC

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehár J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jané-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi P, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–607. doi: 10.1038/nature11003. PubMed DOI PMC

Heneberg P. Redox regulation of hexokinases. Antioxid Redox Signal. 2019;30(3):415–442. doi: 10.1089/ars.2017.7255. PubMed DOI

Cárdenas ML, Cornish-Bowden A, Ureta T. Evolution and regulatory role of the hexokinases. Biochim Biophys Acta. 1998;1401(3):242–264. doi: 10.1016/S0167-4889(97)00150-X. PubMed DOI

Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB. The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate. Structure. 1998;6(1):39–50. doi: 10.1016/S0969-2126(98)00006-9. PubMed DOI

Tseng P, Chen C, Hu K, Cheng H, Lin Y, Tsai W, et al. The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition. Oncotarget. 2018;9(27):18949–18969. doi: 10.18632/oncotarget.24855. PubMed DOI PMC

Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol. 2004;24(13):5923–5936. doi: 10.1128/MCB.24.13.5923-5936.2004. PubMed DOI PMC

Xu S, Zhou T, Doh HM, Tring KR, Catapang A, Lee JT, et al. An HK2 antisense oligonucleotide induces synthetic lethality in HK1-HK2+ multiple myeloma. Cancer Res. 2019;79(10):2748–2760. doi: 10.1158/0008-5472.CAN-18-2799. PubMed DOI PMC

Salani B, Marini C, Del Rio A, Ravera S, Massollo M, Orengo AM, et al. Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase II. Sci Rep. 2013;3(1):2070. doi: 10.1038/srep02070. PubMed DOI PMC

Xintaropoulou C, Ward C, Wise A, Queckborner S, Turnbull A, Michie CO, Williams ARW, Rye T, Gourley C, Langdon SP. Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment. BMC Cancer. 2018;18(1):636. doi: 10.1186/s12885-018-4521-4. PubMed DOI PMC

Guo W, Kuang Y, Wu J, Wen D, Zhou A, Liao Y, Song H, Xu D, Wang T, Jing B, Li K, Hu M, Ling J, Wang Q, Wu W. Hexokinase 2 depletion confers sensitization to metformin and inhibits glycolysis in lung squamous cell carcinoma. Front Oncol. 2020;10:52. doi: 10.3389/fonc.2020.00052. PubMed DOI PMC

DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR, Hay N. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018;9(1):446. doi: 10.1038/s41467-017-02733-4. PubMed DOI PMC

El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–228. doi: 10.1074/jbc.275.1.223. PubMed DOI

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex I of the mitochondrial respiratory chain. Biochem J. 2000;348(3):607–614. doi: 10.1042/bj3480607. PubMed DOI PMC

Javesshghani S, Zakikhani M, Austin S, Bazile M, Blouin MJ, Topisirovic I, et al. Carbon source and Myc expression influence the antiproliferative actions of metformin. Cancer Res. 2012;72(23):6257–6267. doi: 10.1158/0008-5472.CAN-12-2907. PubMed DOI

Liu X, Romero IL, Litchfield LM, Lenguel E, Locasale JW. Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab. 2016;24(5):728–739. doi: 10.1016/j.cmet.2016.09.005. PubMed DOI PMC

Louie MC, Ton J, Brady ML, Le DT, Mar JN, Lerner CA, et al. Total cellular ATP production changes with primary substrate in MCF7 breast cancer cells. Front Oncol. 2020;10:1703. doi: 10.3389/fonc.2020.01703. PubMed DOI PMC

Mendelsohn BA, Bennett NK, Darch MA, Yu K, Nguyen MK, Pucciarelli D, Nelson M, Horlbeck MA, Gilbert LA, Hyun W, Kampmann M, Nakamura JL, Nakamura K. A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy failure. PLoS Biol. 2018;16(8):e2004624. doi: 10.1371/journal.pbio.2004624. PubMed DOI PMC

Muir A, Danai LV, Vander Heiden MG. Microenvironmental regulation of cancer cell metabolism: implications for experimental design and translational studies. Dis Model Mech. 2018;11(8):dmm035758. https://doi.org/10.1242/dmm.035758. PubMed PMC

Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA, Luengo A, Bauer MR, Jha AK, O’Brien JP, Pierce KA, Gui DY, Sullivan LB, Wasylenko TM, Subbaraj L, Chin CR, Stephanopolous G, Mott BT, Jacks T, Clish CB, Vander Heiden MG. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 2016;23(3):517–528. doi: 10.1016/j.cmet.2016.01.007. PubMed DOI PMC

Muir A, Danai LV, Gui DY, Waingarten CY, Lewis CA, Vander Heiden MG. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife. 2017;6:e27713. 10.7554/eLife.27713. PubMed PMC

Hui S, Cowan AJ, Zeng XF, Yang LF, TeSlaa T, Li XX, Bartman C, Zhang Z, Jang C, Wang L, Lu W, Rojas J, Baur J, Rabinowitz JD. Quantitative fluxomics of circulating metabolites. Cell Metab. 2020;32(4):676–688. doi: 10.1016/j.cmet.2020.07.013. PubMed DOI PMC

Allen BG, Bhatia SK, Anderson CM, Eichenberger-Glimore JM, Sibenaller ZA, Mapuskar KA, et al. Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol. 2014;2:963–970. doi: 10.1016/j.redox.2014.08.002. PubMed DOI PMC

Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560(7719):499–503. doi: 10.1038/s41586-018-0343-4. PubMed DOI PMC

Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN, Scheck AC. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer. 2016;16(1):310. doi: 10.1186/s12885-016-2337-7. PubMed DOI PMC

Mavropoulos JC, Buschenmeyer WC, Tewari AK, Rokhfeld D, Pollak M, Zhao Y, et al. The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res. 2009;2(6):557–565. doi: 10.1158/1940-6207.CAPR-08-0188. PubMed DOI PMC

Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, Voelker HU, Thiede A, Coy JF. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer. 2008;8(1):122. doi: 10.1186/1471-2407-8-122. PubMed DOI PMC

Chen L, Zhang Z, Hoshino A, Zheng HD, Morley M, Arany Z, Rabinowitz JD. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat Metab. 2019;1(3):404–415. doi: 10.1038/s42255-019-0043-x. PubMed DOI PMC

Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during stress energy. Nature. 2012;485(7400):661–665. doi: 10.1038/nature11066. PubMed DOI PMC

Hendriks W, Mulders JW, Bibby MA, Slingsby C, Bloemendal H, de Jong WW. Duck lens epsilon-crystallin and lactate dehydrogenase B4 are identical: a single-copy gene product with two distinct functions. Proc Natl Acad Sci USA. 1988;85(19):7114–7118. doi: 10.1073/pnas.85.19.7114. PubMed DOI PMC

Wistow GJ, Lietman T, Williams LA, Stapel SO, De Jong WW, Horwitz J, et al. Tau-crystallin/alpha-enolase: one gene encodes both an enzyme and a lens structural protein. J Cell Biol. 1988;107(6):2729–2736. doi: 10.1083/jcb.107.6.2729. PubMed DOI PMC

Hentze MW, Preiss T. The REM phase of gene regulation. Trends Biochem Sci. 2010;35(8):423–426. doi: 10.1016/j.tibs.2010.05.009. PubMed DOI

Castello A, Hentze MW, Preiss T. Metabolic enzymes enjoying new partnerships as RNA-binding proteins. Trends Endocrinol Metab. 2015;26(12):746–757. doi: 10.1016/j.tem.2015.09.012. PubMed DOI PMC

Kim J-W, Dang CV. Multifaceted roles of glycolytic enzymes. Trends Biochem Sci. 2005;30(3):142–150. doi: 10.1016/j.tibs.2005.01.005. PubMed DOI

Boukouris AE, Zervopoulos SD, Michelakis ED. Metabolic enzymes moonlighting in the nucleus: metabolic regulation of gene transcription. Trends Biochem Sci. 2016;41(8):712–730. doi: 10.1016/j.tibs.2016.05.013. PubMed DOI

Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML, Cho HC, Popescu NI, Coggeshall KM, Arditi M, Underhill DM. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell. 2016;166(3):624–636. doi: 10.1016/j.cell.2016.05.076. PubMed DOI PMC

Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome C release and apoptosis. J Biol Chem. 2002;277(9):7610–7618. doi: 10.1074/jbc.M109950200. PubMed DOI

Mathupala SP, Ko YH, Pedersen PL. Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene. 2006;25(34):4777–4786. doi: 10.1038/sj.onc.1209603. PubMed DOI PMC

Rodríguez-Saavedra C, Morgado-Martínez LE, Burgos-Palacios A, King-Díaz B, López-Coria M, Sánchez-Nieto S. Moonlighting proteins: the case of the hexokinases. Front Mol Biosci. 2021;8:701975. doi: 10.3389/fmolb.2021.701975. PubMed DOI PMC

Metabolism of primary high-grade serous ovarian carcinoma (HGSOC) cells under limited glutamine or glucose availability