Critical role of mTOR in regulating aerobic glycolysis in carcinogenesis (Review)
- Authors:
- Hui Fan
- Yuanyuan Wu
- Suyun Yu
- Xiaoman Li
- Aiyun Wang
- Shijun Wang
- Wenxing Chen
- Yin Lu
-
Affiliations: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China, Shandong Co‑innovation Center of TCM Formula, College of TCM, Shandong University of TCM, Jinan, Shandong 250355, P.R. China - Published online on: November 25, 2020 https://doi.org/10.3892/ijo.2020.5152
- Pages: 9-19
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Abstract
Vander Heiden MG and DeBerardinis RJ: Understanding the intersections between metabolism and cancer biology. Cell. 168:657–669. 2017. View Article : Google Scholar : PubMed/NCBI | |
Vijayakrishnapillai LMK, Desmarais JS, Groeschen MN and Perlin MH: Deletion of ptn1, a PTEN/TEP1 orthologue, in ustilago maydis reduces pathogenicity and teliospore development. J Fungi (Basel). 5:12018. View Article : Google Scholar | |
Huang S, Yang C, Li M, Wang B, Chen H, Fu D and Chong T: Effect of dual mTOR inhibitor on TGFβ1-induced fibrosis in primary human urethral scar fibroblasts. Biomed Pharmacother. 106:1182–1187. 2018. View Article : Google Scholar : PubMed/NCBI | |
Mossmann D, Park S and Hall MN: mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 18:744–757. 2018. View Article : Google Scholar : PubMed/NCBI | |
Kenerson HL, Aicher LD, True LD and Yeung RS: Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 62:5645–5650. 2002.PubMed/NCBI | |
Dowling RJ, Topisirovic I, Fonseca BD and Sonenberg N: Dissecting the role of mTOR: Lessons from mTOR inhibitors. Biochim Biophys Acta. 1804:433–439. 2010. View Article : Google Scholar | |
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P and Sabatini DM: mTOR inter-acts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 110:163–175. 2002. View Article : Google Scholar : PubMed/NCBI | |
Hara K, Maruki Y, Long X, Yoshino KI, Oshiro N, Hidayat S, Tokunaga C, Avruch J and Yonezawa K: Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 110:177–189. 2002. View Article : Google Scholar : PubMed/NCBI | |
Saxton RA and Sabatini DM: mTOR signaling in growth, metabolism, and disease. Cell. 169:361–371. 2017. View Article : Google Scholar : PubMed/NCBI | |
Liu GY and Sabatini DM: mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 21:183–203. 2020. View Article : Google Scholar : PubMed/NCBI | |
Hayase S, Kumamoto K, Saito K, Kofunato Y, Sato Y, Okayama H, Miyamoto K, Ohki S and Takenoshita S: L-type amino acid transporter 1 expression is upregulated and associated with cellular proliferation in colorectal cancer. Oncol Lett. 14:7410–7416. 2017. | |
Villar VH, Nguyen TL, Delcroix V, Terés S, Bouchecareilh M, Salin B, Bodineau C, Vacher P, Priault M, Soubeyran P and Durán RV: mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation. Nat Commun. 8:141242017. View Article : Google Scholar : PubMed/NCBI | |
van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, et al: Modulation of glutamine metabolism by the PI(3) K-PKB-FOXO network regulates autophagy. Nat Cell Biol. 14:829–837. 2012. View Article : Google Scholar : PubMed/NCBI | |
Wise DR and Thompson CB: Glutamine addiction: A new therapeutic target in cancer. Trends Biochem Sci. 35:427–433. 2010. View Article : Google Scholar : PubMed/NCBI | |
Li J, Huang Q, Long X, Zhang J, Huang X, Aa J, Yang H, Chen Z and Xing J: CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways. J Hepatol. 63:1378–1389. 2015. View Article : Google Scholar : PubMed/NCBI | |
Harachi M, Masui K, Okamura Y, Tsukui R, Mischel PS and Shibata N: mTOR complexes as a nutrient sensor for driving cancer progression. Int J Mol Sci. 19:32672018. View Article : Google Scholar : | |
Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI | |
Ganapathy-Kanniappan S: Molecular intricacies of aerobic glycolysis in cancer: Current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol. 53:667–682. 2018. View Article : Google Scholar | |
Chen XS, Li LY, Guan YD, Yang JM and Cheng Y: Anticancer strategies based on the metabolic profile of tumor cells: Therapeutic targeting of the Warburg effect. Acta Pharmacol Sin. 37:1013–1019. 2016. View Article : Google Scholar : PubMed/NCBI | |
Lei S, Yang J, Chen C, Sun J, Yang L, Tang H, Yang T, Chen A, Zhao H, Li Y and Du X: FLIP(L) is critical for aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 35:792016. View Article : Google Scholar : PubMed/NCBI | |
Shi Y, Liu S, Ahmad S and Gao Q: Targeting key transporters in tumor glycolysis as a novel anticancer strategy. Curr Top Med Chem. 18:454–466. 2018. View Article : Google Scholar : PubMed/NCBI | |
Liu B and Yu S: Amentoflavone suppresses hepatocellular carcinoma by repressing hexokinase 2 expression through inhibiting JAK2/STAT3 signaling. Biomed Pharmacother. 107:243–253. 2018. View Article : Google Scholar : PubMed/NCBI | |
Gao X and Han H: Jolkinolide B inhibits glycolysis by down-regulating hexokinase 2 expression through inactivating the Akt/mTOR pathway in non-small cell lung cancer cells. J Cell Biochem. 119:4967–4974. 2018. View Article : Google Scholar : PubMed/NCBI | |
Liu B, Huang ZB, Chen X, See YX, Chen ZK and Yao HK: Mammalian target of rapamycin 2 (MTOR2) and C-MYC modulate glucosamine-6-phosphate synthesis in glioblastoma (GBM) cells through glutamine: Fructose-6-phosphate aminotransferase 1 (GFAT1). Cell Mol Neurobiol. 39:415–434. 2019. View Article : Google Scholar : PubMed/NCBI | |
Ghashghaeinia M, Koberle M, Mrowietz U and Bernhardt I: Proliferating tumor cells mimick glucose metabolism of mature human erythrocytes. Cell Cycle. 18:1316–1334. 2019. View Article : Google Scholar : PubMed/NCBI | |
Prakasam G, Singh RK, Iqbal MA, Saini SK, Tiku AB and Bamezai RNK: Pyruvate kinase M knockdown-induced signaling via AMP-activated protein kinase promotes mitochondrial biogenesis, autophagy, and cancer cell survival. J Biol Chem. 292:15561–15576. 2017. View Article : Google Scholar : PubMed/NCBI | |
Wang R, Jiao H, Zhao J, Wang X and Lin H: L-arginine enhances protein synthesis by phosphorylating mTOR (Thr 2446) in a nitric oxide-dependent manner in C2C12 cells. Oxid Med Cell Longev. 2018:75691272018. View Article : Google Scholar : PubMed/NCBI | |
Ka M, Smith AL and Kim WY: MTOR controls genesis and autophagy of GABAergic interneurons during brain development. Autophagy. 13:1348–1363. 2017. View Article : Google Scholar : PubMed/NCBI | |
Caron A, Briscoe DM, Richard D and Laplante M: DEPTOR at the nexus of cancer, metabolism, and immunity. Physiol Rev. 98:1765–1803. 2018. View Article : Google Scholar : PubMed/NCBI | |
Payen VL, Porporato PE, Baselet B and Sonveaux P: Metabolic changes associated with tumor metastasis, part 1: Tumor pH, glycolysis and the pentose phosphate pathway. Cell Mol Life Sci. 73:1333–1348. 2016. View Article : Google Scholar | |
Li L, Kang L, Zhao W, Feng Y, Liu W, Wang T, Mai H, Huang J, Chen S, Liang Y, et al: miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect. Cancer Lett. 400:89–98. 2017. View Article : Google Scholar : PubMed/NCBI | |
Zoncu R, Efeyan A and Sabatini DM: mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 12:21–35. 2011. View Article : Google Scholar | |
Wyant GA, Abu-Remaileh M, Wolfson RL, Chen WW, Freinkman E, Danai LV, Vander Heiden MG and Sabatini DM: mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell. 171:642–654 e612. 2017. View Article : Google Scholar : PubMed/NCBI | |
Feng M, Xiong G, Cao Z, Yang G, Zheng S, Qiu J, You L, Zheng L, Zhang T and Zhao Y: LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer. J Exp Clin Cancer Res. 37:2742018. View Article : Google Scholar : PubMed/NCBI | |
Yoshida S, Pacitto R, Yao Y, Inoki K and Swanson JA: Growth factor signaling to mTORC1 by amino acid-laden macropinosomes. J Cell Biol. 211:159–172. 2015. View Article : Google Scholar : PubMed/NCBI | |
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB and Cohen P: Characterization of a 3-phos-phoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 7:261–269. 1997. View Article : Google Scholar : PubMed/NCBI | |
Iqbal MA, Siddiqui FA, Gupta V, Chattopadhyay S, Gopinath P, Kumar B, Manvati S, Chaman N and Bamezai RNK: Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer. 12:722013. View Article : Google Scholar : PubMed/NCBI | |
Neil J, Shannon C, Mohan A, Laurent D, Murali R and Jhanwar-Uniyal M: ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma. Int J Oncol. 48:1045–1052. 2016. View Article : Google Scholar : PubMed/NCBI | |
Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, Dhar A and Pavletich NP: Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 552:368–373. 2017. View Article : Google Scholar : PubMed/NCBI | |
Ma Y, Vassetzky Y and Dokudovskaya S: mTORC1 pathway in DNA damage response. Biochim Biophys Acta Mol Cell Res. 1865:1293–1311. 2018. View Article : Google Scholar : PubMed/NCBI | |
Dewar JM and Walter JC: Mechanisms of DNA replication termination. Nat Rev Mol Cell Biol. 18:507–516. 2017. View Article : Google Scholar : PubMed/NCBI | |
Hsieh HJ, Zhang W, Lin SH, Yang WH, Wang JZ, Shen J, Zhang Y, Lu Y, Wang H, Yu J, et al: Systems biology approach reveals a link between mTORC1 and G2/M DNA damage check-point recovery. Nat Commun. 9:39822018. View Article : Google Scholar | |
Silvera D, Ernlund A, Arju R, Connolly E, Volta V, Wang J and Schneider RJ: mTORC1 and -2 coordinate transcriptional and translational reprogramming in resistance to DNA damage and replicative stress in breast cancer cells. Mol Cell Biol. 37:e005772017. View Article : Google Scholar : | |
Javary J, Allain-Courtois N, Saucisse N, Costet P, Heraud C, Benhamed F, Pierre R, Bure C, Pallares-Lupon N, Do Cruzeiro M, et al: Liver reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling. Gut. 67:2192–2203. 2018. View Article : Google Scholar | |
Byun JK, Choi YK, Kim JH, Jeong JY, Jeon HJ, Kim MK, Hwang I, Lee SY, Lee YM, Lee IK and Park KG: A positive feedback loop between sestrin2 and mTORC2 is required for the survival of glutamine-depleted lung cancer cells. Cell Rep. 20:586–599. 2017. View Article : Google Scholar : PubMed/NCBI | |
Yuan T, Lupse B, Maedler K and Ardestani A: mTORC2 signaling: A path for pancreatic β cell's growth and function. J Mol Biol. 430:904–918. 2018. View Article : Google Scholar : PubMed/NCBI | |
Zhang J, Jia L, Liu T, Yip YL, Tang WC, Lin W, Deng W, Lo KW, You C, Lung ML, et al: mTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma. Oncogene. 38:4669–4684. 2019. View Article : Google Scholar : PubMed/NCBI | |
Li W, Wong CC, Zhang X, Kang W, Nakatsu G, Zhao Q, Chen H, Go MYY, Chiu PWY, Wang X, et al: CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1α axis to inhibit gastric tumorigenesis. Oncogene. 37:6383–6398. 2018. View Article : Google Scholar : PubMed/NCBI | |
Varshney R, Gupta S and Roy P: Cytoprotective effect of kaempferol against palmitic acid-induced pancreatic β-cell death through modulation of autophagy via AMPK/mTOR signaling pathway. Mol Cell Endocrinol. 448:1–20. 2017. View Article : Google Scholar : PubMed/NCBI | |
Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, et al: AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17:113–124. 2013. View Article : Google Scholar : PubMed/NCBI | |
Daurio NA, Tuttle SW, Worth AJ, Song EY, Davis JM, Snyder NW, Blair IA and Koumenis C: AMPK activation and metabolic repro-gramming by tamoxifen through estrogen receptor-independent mechanisms suggests new uses for this therapeutic modality in cancer treatment. Cancer Res. 76:3295–3306. 2016. View Article : Google Scholar : PubMed/NCBI | |
Han J, Zhang L, Guo H, Wysham WZ, Roque DR, Willson AK, Sheng X, Zhou C and Bae-Jump VL: Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling. Gynecol Oncol. 138:668–675. 2015. View Article : Google Scholar : PubMed/NCBI | |
Liu Y, Tong L, Luo Y, Li X, Chen G and Wang Y: Resveratrol inhibits the proliferation and induces the apoptosis in ovarian cancer cells via inhibiting glycolysis and targeting AMPK/mTOR signaling pathway. J Cell Biochem. 119:6162–6172. 2018. View Article : Google Scholar : PubMed/NCBI | |
Liang J and Mills GB: AMPK: A contextual oncogene or tumor suppressor? Cancer Res. 73:2929–2935. 2013. View Article : Google Scholar : PubMed/NCBI | |
Hauge M, Bruserud O and Hatfield KJ: Targeting of cell metabolism in human acute myeloid leukemia-more than targeting of isocitrate dehydrogenase mutations and PI3K/AKT/mTOR signaling? Eur J Haematol. 96:211–221. 2016. View Article : Google Scholar | |
Yang X, Cheng Y, Li P, Tao J, Deng X, Zhang X, Gu M, Lu Q and Yin C: A lentiviral sponge for miRNA-21 dimin-ishes aerobic glycolysis in bladder cancer T24 cells via the PTEN/PI3K/AKT/mTOR axis. Tumour Biol. 36:383–391. 2015. View Article : Google Scholar | |
Wang P, Guan Q, Zhou D, Yu Z, Song Y and Qiu W: miR-21 inhibitors modulate biological functions of gastric cancer cells via PTEN/PI3K/mTOR pathway. DNA Cell Biol. 37:38–45. 2018. View Article : Google Scholar | |
Wang WJ, Yang W, Ouyang ZH, Xue JB, Li XL, Zhang J, He WS, Chen WK, Yan YG and Wang C: MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells. Biomed Pharmacother. 99:725–734. 2018. View Article : Google Scholar : PubMed/NCBI | |
Makinoshima H, Takita M, Saruwatari K, Umemura S, Obata Y, Ishii G, Matsumoto S, Sugiyama E, Ochiai A, Abe R, et al: Signaling through the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) axis is responsible for aerobic glycolysis mediated by glucose transporter in epidermal growth factor receptor (EGFR)-mutated lung adeno-carcinoma. J Biol Chem. 290:17495–17504. 2015. View Article : Google Scholar : PubMed/NCBI | |
Fruman DA and Rommel C: PI3K and cancer: Lessons, challenges and opportunities. Nat Rev Drug Discov. 13:140–156. 2014. View Article : Google Scholar : PubMed/NCBI | |
Li Q, Tang H, Hu F and Qin C: Silencing of FOXO6 inhibits the proliferation, invasion, and glycolysis in colorectal cancer cells. J Cell Biochem. 120:3853–3860. 2019. View Article : Google Scholar | |
Gong T, Cui L, Wang H, Wang H and Han N: Knockdown of KLF5 suppresses hypoxia-induced resistance to cisplatin in NSCLC cells by regulating HIF-1α-dependent glycolysis through inactivation of the PI3K/Akt/mTOR pathway. J Transl Med. 16:1642018. View Article : Google Scholar | |
Xu DH, Li Q, Hu H, Ni B, Liu X, Huang C, Zhang ZZ and Zhao G: Transmembrane protein GRINA modulates aerobic glycolysis and promotes tumor progression in gastric cancer. J Exp Clin Cancer Res. 37:3082018. View Article : Google Scholar : PubMed/NCBI | |
Li X, Zhang Y, Ma W, Fu Q, Liu J, Yin G, Chen P, Dai D, Chen W, Qi L, et al: Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma. Cancer Immunol Immunother. 69:535–548. 2020. View Article : Google Scholar : PubMed/NCBI | |
Li Z, Liu J, Que L and Tang X: The immunoregulatory protein B7-H3 promotes aerobic glycolysis in oral squamous carcinoma via PI3K/Akt/mTOR pathway. J Cancer. 10:5770–5784. 2019. View Article : Google Scholar : PubMed/NCBI | |
Li R, Weng L, Liu B, Zhu L, Zhang X, Tian G, Hu L, Li Q, Jiang S and Shang M: TRIM59 predicts poor prognosis and promotes pancreatic cancer progression via the PI3K/AKT/mTOR-glycolysis signaling axis. J Cell Biochem. 121:1986–1997. 2020. View Article : Google Scholar | |
Peng W, Huang W, Ge X, Xue L, Zhao W and Xue J: Type Ig phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer. EBioMedicine. 44:375–386. 2019. View Article : Google Scholar : PubMed/NCBI | |
Li D, Ji H, Niu X, Yin L, Wang Y, Gu Y, Wang J, Zhou X, Zhang H and Zhang Q: Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer. Cancer Sci. 111:47–58. 2020. View Article : Google Scholar | |
Gasparri ML, Besharat ZM, Farooqi AA, Khalid S, Taghavi K, Besharat RA, Sabato C, Papadia A, Panici PB, Mueller MD and Ferretti E: MiRNAs and their interplay with PI3K/AKT/mTOR pathway in ovarian cancer cells: A potential role in platinum resistance. J Cancer Res Clin Oncol. 144:2313–2318. 2018. View Article : Google Scholar : PubMed/NCBI | |
Deng J, Bai X, Feng X, Ni J, Beretov J, Graham P and Li Y: Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer. 19:6182019. View Article : Google Scholar : PubMed/NCBI | |
Massari F, Ciccarese C, Santoni M, Iacovelli R, Mazzucchelli R, Piva F, Scarpelli M, Berardi R, Tortora G, Lopez-Beltran A, et al: Metabolic phenotype of bladder cancer. Cancer Treat Rev. 45:46–57. 2016. View Article : Google Scholar : PubMed/NCBI | |
Wang Y, Han X, Fu M, Wang J, Song Y, Liu Y, Zhang J, Zhou J and Ge J: Qiliqiangxin attenuates hypoxia-induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF-1α-dependent glycolysis. J Cell Mol Med. 22:2791–2803. 2018. View Article : Google Scholar : PubMed/NCBI | |
Koh YW, Lee SJ and Park SY: Differential expression and prognostic significance of GLUT1 according to histologic type of non-small-cell lung cancer and its association with volume-dependent parameters. Lung Cancer. 104:31–37. 2017. View Article : Google Scholar : PubMed/NCBI | |
Hamann I, Krys D, Glubrecht D, Bouvet V, Marshall A, Vos L, Mackey JR, Wuest M and Wuest F: Expression and function of hexose transporters GLUT1, GLUT2, and GLUT5 in breast cancer-effects of hypoxia. FASEB J. 32:5104–5118. 2018. View Article : Google Scholar : PubMed/NCBI | |
Buller CL, Loberg RD, Fan MH, Zhu Q, Park JL, Vesely E, Inoki K, Guan KL and Brosius FC III: A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose trans-porter expression. Am J Physiol Cell Physiol. 295:C836–C843. 2008. View Article : Google Scholar : PubMed/NCBI | |
Jiang X, Kenerson H, Aicher L, Miyaoka R, Eary J, Bissler J and Yeung RS: The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake. Am J Pathol. 172:1748–1756. 2008. View Article : Google Scholar : PubMed/NCBI | |
Wu XL, Wang LK, Yang DD, Qu M, Yang YJ, Guo F, Han L and Xue J: Effects of Glut1 gene silencing on proliferation, differentiation, and apoptosis of colorectal cancer cells by targeting the TGF-β/PI3K-AKT-mTOR signaling pathway. J Cell Biochem. 119:2356–2367. 2018. View Article : Google Scholar | |
Barron CC, Bilan PJ, Tsakiridis T and Tsiani E: Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism. 65:124–139. 2016. View Article : Google Scholar : PubMed/NCBI | |
Do SK, Jeong JY, Lee SY, Choi JE, Hong MJ, Kang HG, Lee WK, Seok Y, Lee EB, Shin KM, et al: Glucose transporter 1 gene variants predict the prognosis of patients with early-stage non-small cell lung cancer. Ann Surg Oncol. 25:3396–3403. 2018. View Article : Google Scholar : PubMed/NCBI | |
Zha X, Hu Z, Ji S, Jin F, Jiang K, Li C, Zhao P, Tu Z, Chen X, Di L, et al: NFκB up-regulation of glucose transporter 3 is essential for hyperactive mammalian target of rapamycin-induced aerobic glycolysis and tumor growth. Cancer Lett. 359:97–106. 2015. View Article : Google Scholar : PubMed/NCBI | |
DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR and Hay N: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 9:4462018. View Article : Google Scholar : PubMed/NCBI | |
Hay N: Reprogramming glucose metabolism in cancer: Can it be exploited for cancer therapy? Nat Rev Cancer. 16:635–649. 2016. View Article : Google Scholar : PubMed/NCBI | |
Esteves JV, Yonamine CY, Pinto-Junior DC, Gerlinger-Romero F, Enguita FJ and Machado UF: Diabetes modulates MicroRNAs 29b-3p, 29c-3p, 199a-5p and 532-3p expression in muscle: Possible role in GLUT4 and HK2 repression. Front Endocrinol (Lausanne). 9:5362018. View Article : Google Scholar | |
Marampon F, Antinozzi C, Corinaldesi C, Vannelli GB, Sarchielli E, Migliaccio S, Di Luigi L, Lenzi A and Crescioli C: The phosphodiesterase 5 inhibitor tadalafil regulates lipidic homeostasis in human skeletal muscle cell metabolism. Endocrine. 59:602–613. 2018. View Article : Google Scholar | |
DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR and Hay N: Author correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 9:25392018. View Article : Google Scholar : PubMed/NCBI | |
Kudryavtseva AV, Fedorova MS, Zhavoronkov A, Moskalev AA, Zasedatelev AS, Dmitriev AA, Sadritdinova AF, Karpova IY, Nyushko KM, Kalinin DV, et al: Effect of lentivirus-mediated shRNA inactivation of HK1, HK2, and HK3 genes in colorectal cancer and melanoma cells. BMC Genet. 17(Suppl 3): S1562016. View Article : Google Scholar | |
Pudova EA, Kudryavtseva AV, Fedorova MS, Zaretsky AR, Shcherbo DS, Lukyanova EN, Popov AY, Sadritdinova AF, Abramov IS, Kharitonov SL, et al: HK3 overexpression associated with epithelial-mesenchymal transition in colorectal cancer. BMC Genomics. 19(Suppl 3): S1132018. View Article : Google Scholar | |
Fujieda H, Kogami M, Sakairi M, Kato N, Makino M, Takahashi N, Miyazawa T, Harada S and Yamashita T: Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus. Eur J Med Chem. 156:269–294. 2018. View Article : Google Scholar : PubMed/NCBI | |
Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, et al: Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity. 47:875–889 e10. 2017. View Article : Google Scholar : PubMed/NCBI | |
Yeung SJ, Pan J and Lee MH: Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol Life Sci. 65:3981–3999. 2008. View Article : Google Scholar : PubMed/NCBI | |
Roberts DJ and Miyamoto S: Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 22:3642015. View Article : Google Scholar : PubMed/NCBI | |
Conde E, Giménez-Moyano S, Martín-Gómez L, Rodríguez M, Ramos ME, Aguado-Fraile E, Blanco-Sanchez I, Saiz A and García-Bermejo ML: HIF-1α induction during reperfusion avoids maladaptive repair after renal ischemia/reperfusion involving miR127-3p. Sci Rep. 7:410992017. View Article : Google Scholar | |
Zhang T, Zhu X, Wu H, Jiang K, Zhao G, Shaukat A, Deng G and Qiu C: Targeting the ROS/PI3K/AKT/HIF-1α/HK2 axis of breast cancer cells: Combined administration of polydatin and 2-deoxy-d-glucose. J Cell Mol Med. 23:3711–3723. 2019. View Article : Google Scholar : PubMed/NCBI | |
Miyazaki M, Miyazaki K, Chen S, Chandra V, Wagatsuma K, Agata Y, Rodewald HR, Saito R, Chang AN, Varki N, et al: The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis. Genes Dev. 29:409–425. 2015. View Article : Google Scholar : PubMed/NCBI | |
Sudhagar S, Sathya S and Lakshmi BS: Rapid non-genomic signalling by 17β-oestradiol through c-Src involves mTOR-dependent expression of HIF-1α in breast cancer cells. Br J Cancer. 105:953–960. 2011. View Article : Google Scholar : PubMed/NCBI | |
Huang C, Bruggeman LA, Hydo LM and Miller RT: Shear stress induces cell apoptosis via a c-Src-phospholipase D-mTOR signaling pathway in cultured podocytes. Exp Cell Res. 318:1075–1085. 2012. View Article : Google Scholar : PubMed/NCBI | |
Zhang J, Wang S, Jiang B, Huang L, Ji Z, Li X, Zhou H, Han A, Chen A, Wu Y, et al: c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis. Nat Commun. 8:137322017. View Article : Google Scholar : PubMed/NCBI | |
Zhang K, Zhang M, Jiang H, Liu F, Liu H and Li Y: Down-regulation of miR-214 inhibits proliferation and glycolysis in non-small-cell lung cancer cells via down-regulating the expression of hexokinase 2 and pyruvate kinase isozyme M2. Biomed Pharmacother. 105:545–552. 2018. View Article : Google Scholar : PubMed/NCBI | |
Singh D, Arora R, Kaur P, Singh B, Mannan R and Arora S: Overexpression of hypoxia-inducible factor and metabolic path-ways: Possible targets of cancer. Cell Biosci. 7:622017. View Article : Google Scholar | |
Webb BA, Forouhar F, Szu FE, Seetharaman J, Tong L and Barber DL: Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations. Nature. 523:111–114. 2015. View Article : Google Scholar : PubMed/NCBI | |
Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA III, Peters EC, Driggers EM and Hsieh-Wilson LC: Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 337:975–980. 2012. View Article : Google Scholar : PubMed/NCBI | |
Moreno-Sánchez R, Marin-Hernández A, Gallardo-Pérez JC, Quezada H, Encalada R, Rodríguez-Enríquez S and Saavedra E: Phosphofructokinase type 1 kinetics, isoform expression, and gene polymorphisms in cancer cells. J Cell Biochem. 113:1692–1703. 2012.PubMed/NCBI | |
Lee JH, Liu R, Li J, Zhang C, Wang Y, Cai Q, Qian X, Xia Y, Zheng Y, Piao Y, et al: Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun. 8:9492017. View Article : Google Scholar : PubMed/NCBI | |
Tang H, Lee M, Sharpe O, Salamone L, Noonan EJ, Hoang CD, Levine S, Robinson WH and Shrager JB: Oxidative stress-responsive microRNA-320 regulates glycolysis in diverse biological systems. FASEB J. 26:4710–4721. 2012. View Article : Google Scholar : PubMed/NCBI | |
Gomez LS, Zancan P, Marcondes MC, Ramos-Santos L, Meyer-Fernandes JR, Sola-Penna M and Da Silva D: Resveratrol decreases breast cancer cell viability and glucose metabolism by inhibiting 6-phosphofructo-1-kinase. Biochimie. 95:1336–1343. 2013. View Article : Google Scholar : PubMed/NCBI | |
Holmes B, Lee J, Landon KA, Benavides-Serrato A, Bashir T, Jung ME, Lichtenstein A and Gera J: Mechanistic target of rapamycin (mTOR) inhibition synergizes with reduced internal ribosome entry site (IRES)-mediated translation of cyclin D1 and c-MYC mRNAs to treat glioblastoma. J Biol Chem. 291:14146–14159. 2016. View Article : Google Scholar : PubMed/NCBI | |
Bartrons R, Simon-Molas H, Rodríguez-Garcia A, Castaño E, Navarro-Sabaté À, Manzano A and Martinez-Outschoorn UE: Fructose 2,6-bisphosphate in cancer cell metabolism. Front Oncol. 8:3312018. View Article : Google Scholar : PubMed/NCBI | |
Wang C, Qu J, Yan S, Gao Q, Hao S and Zhou D: PFK15, a PFKFB3 antagonist, inhibits autophagy and proliferation in rhabdomyosarcoma cells. Int J Mol Med. 42:359–367. 2018.PubMed/NCBI | |
Ros S and Schulze A: Balancing glycolytic flux: The role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab. 1:82013. View Article : Google Scholar : PubMed/NCBI | |
Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, et al: Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell. 30:968–985. 2016. View Article : Google Scholar : PubMed/NCBI | |
Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R and Bucala R: High expression of inducible 6-phos-phofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 62:5881–5887. 2002.PubMed/NCBI | |
Feng Y and Wu L: mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival. Biochem Biophys Res Commun. 483:897–903. 2017. View Article : Google Scholar : PubMed/NCBI | |
Ziegler ME, Hatch MM, Wu N, Muawad SA and Hughes CC: mTORC2 mediates CXCL12-induced angiogenesis. Angiogenesis. 19:359–371. 2016. View Article : Google Scholar : PubMed/NCBI | |
Shi L, Pan H, Liu Z, Xie J and Han W: Roles of PFKFB3 in cancer. Signal Transduct Target Ther. 2:170442017. View Article : Google Scholar : PubMed/NCBI | |
Dasgupta S, Rajapakshe K, Zhu B, Nikolai BC, Yi P, Putluri N, Choi JM, Jung SY, Coarfa C, Westbrook TF, et al: Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 556:249–254. 2018. View Article : Google Scholar : PubMed/NCBI | |
Zhang H, Lu C, Fang M, Yan W, Chen M, Ji Y, He S, Liu T, Chen T and Xiao J: HIF-1α activates hypoxia-induced PFKFB4 expression in human bladder cancer cells. Biochem Biophys Res Commun. 476:146–152. 2016. View Article : Google Scholar : PubMed/NCBI | |
Zhang Z, Deng X, Liu Y, Liu Y, Sun L and Chen F: PKM2, function and expression and regulation. Cell Biosci. 9:522019. View Article : Google Scholar : PubMed/NCBI | |
Nguyen A, Loo JM, Mital R, Weinberg EM, Man FY, Zeng Z, Paty PB, Saltz L, Janjigian YY, de Stanchina E and Tavazoie SF: PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis. J Clin Invest. 126:681–694. 2016. View Article : Google Scholar : PubMed/NCBI | |
Adem S, Comakli V and Uzun N: Pyruvate kinase activators as a therapy target: A patent review 2011-2017. Expert Opin Ther Pat. 28:61–68. 2018. View Article : Google Scholar | |
Liu VM and Vander Heiden MG: The role of pyruvate kinase M2 in cancer metabolism. Brain Pathol. 25:781–783. 2015. View Article : Google Scholar : PubMed/NCBI | |
Warner SL, Carpenter KJ and Bearss DJ: Activators of PKM2 in cancer metabolism. Future Med Chem. 6:1167–1178. 2014. View Article : Google Scholar : PubMed/NCBI | |
Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung HJ and Wang WC: JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci USA. 111:279–284. 2014. View Article : Google Scholar | |
Kim DJ, Park YS, Kim ND, Min SH, You YM, Jung Y, Koo H, Noh H, Kim JA, Park KC and Yeom YI: A novel pyruvate kinase M2 activator compound that suppresses lung cancer cell viability under hypoxia. Mol Cells. 38:373–379. 2015. View Article : Google Scholar : PubMed/NCBI | |
Huang L, Yu Z, Zhang Z, Ma W, Song S and Huang G: Interaction with pyruvate kinase M2 destabilizes tristetraprolin by proteasome degradation and regulates cell proliferation in breast cancer. Sci Rep. 6:224492016. View Article : Google Scholar : PubMed/NCBI | |
Wang C, Jiang J, Ji J, Cai Q, Chen X, Yu Y, Zhu Z and Zhang J: PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. Sci Rep. 7:28862017. View Article : Google Scholar : PubMed/NCBI | |
van Niekerk G and Engelbrecht AM: Role of PKM2 in directing the metabolic fate of glucose in cancer: A potential therapeutic target. Cell Oncol (Dordr). 41:343–351. 2018. View Article : Google Scholar | |
Nemazanyy I, Espeillac C, Pende M and Panasyuk G: Role of PI3K, mTOR and Akt2 signalling in hepatic tumorigenesis via the control of PKM2 expression. Biochem Soc Trans. 41:917–922. 2013. View Article : Google Scholar : PubMed/NCBI | |
Moloughney JG, Kim PK, Vega-Cotto NM, Wu CC, Zhang S, Adlam M, Lynch T, Chou PC, Rabinowitz JD, Werlen G and Jacinto E: mTORC2 responds to glutamine catabolite levels to modulate the hexosamine biosynthesis enzyme GFAT1. Mol Cell. 63:811–826. 2016. View Article : Google Scholar : PubMed/NCBI | |
Gupta A, Ajith A, Singh S, Panday RK, Samaiya A and Shukla S: PAK2-c-Myc-PKM2 axis plays an essential role in head and neck oncogenesis via regulating Warburg effect. Cell Death Dis. 9:8252018. View Article : Google Scholar : PubMed/NCBI | |
Xiaoyu H, Yiru Y, Shuisheng S, Keyan C, Zixing Y, Shanglin C, Yuan W, Dongming C, Wangliang Z, Xudong B and Jie M: The mTOR pathway regulates PKM2 to affect glycolysis in esophageal squamous cell carcinoma. Technol Cancer Res Treat. 17:15330338187800632018. View Article : Google Scholar : PubMed/NCBI | |
Zhang X, Li Y, Ma Y, Yang L, Wang T, Meng X, Zong Z, Sun X, Hua X and Li H: Yes-associated protein (YAP) binds to HIF-1 α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress. J Exp Clin Cancer Res. 37:2162018. View Article : Google Scholar | |
Demaria M and Poli V: PKM2, STAT3 and HIF-1α: The Warburg's vicious circle. JAKSTAT. 1:194–196. 2012.PubMed/NCBI | |
Gao S, Chen M, Wei W, Zhang X, Zhang M, Yao Y, Lv Y, Ling T, Wang L and Zou X: Crosstalk of mTOR/PKM2 and STAT3/c-Myc signaling pathways regulate the energy metabolism and acidic microenvironment of gastric cancer. J Cell Biochem. 2018.Epub ahead of print. | |
Mendez-Lucas A, Li X, Hu J, Che L, Song X, Jia J, Wang J, Xie C, Driscoll PC, Tschaharganeh DF, et al: Glucose catabolism in liver tumors induced by c-MYC can be sustained by various PKM1/PKM2 ratios and pyruvate kinase activities. Cancer Res. 77:4355–4364. 2017. View Article : Google Scholar : PubMed/NCBI | |
Yu P, Li AX, Chen XS, Tian M, Wang HY, Wang XL, Zhang Y, Wang KS and Cheng Y: PKM2-c-Myc-survivin cascade regulates the cell proliferation, migration, and tamoxifen resistance in breast cancer. Front Pharmacol. 11:5504692020. View Article : Google Scholar : PubMed/NCBI | |
Alves MM, Fuhler GM, Queiroz KC, Scholma J, Goorden S, Anink J, Spek CA, Hoogeveen-Westerveld M, Bruno MJ, Nellist M, et al: PAK2 is an effector of TSC1/2 signaling independent of mTOR and a potential therapeutic target for tuberous sclerosis complex. Sci Rep. 5:145342015. View Article : Google Scholar : PubMed/NCBI | |
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Zhan L, Guo JY, et al: Glucose feeds the TCA cycle via circulating lactate. Nature. 551:115–118. 2017. View Article : Google Scholar : PubMed/NCBI | |
Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, Yang C, Do QN, Doucette S, Burguete D, et al: Lactate metabolism in human lung tumors. Cell. 171:358–371 e359. 2017. View Article : Google Scholar : PubMed/NCBI | |
Allen E, Mieville P, Warren CM, Saghafinia S, Li L, Peng MW and Hanahan D: Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep. 15:1144–1160. 2016. View Article : Google Scholar : PubMed/NCBI | |
Kim HK, Lee I, Bang H, Kim HC, Lee WY, Yun SH, Lee J, Lee SJ, Park YS, Kim KM and Kang WK: MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis. Mol Cancer Ther. 17:838–848. 2018. View Article : Google Scholar : PubMed/NCBI | |
Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, Hess C and Christofori G: Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep. 15:1161–1174. 2016. View Article : Google Scholar : PubMed/NCBI | |
Morrot A, da Fonseca LM, Salustiano EJ, Gentile LB, Conde L, Filardy AA, Franklim TN, da Costa KM, Freire-de-Lima CG and Freire-de-Lima L: Metabolic symbiosis and immunomodulation: How tumor cell-derived lactate may disturb innate and adaptive immune responses. Front Oncol. 8:812018. View Article : Google Scholar : PubMed/NCBI | |
Pavlova NN and Thompson CB: The emerging hallmarks of cancer metabolism. Cell Metab. 23:27–47. 2016. View Article : Google Scholar : PubMed/NCBI | |
Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, Leiby B, Cognetti DM, Sotgia F, Lisanti MP and Martinez-Outschoorn UE: Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle. 12:1371–1384. 2013. View Article : Google Scholar : PubMed/NCBI | |
Luo F, Zou Z, Liu X, Ling M, Wang Q, Wang Q, Lu L, Shi L, Liu Y, Liu Q and Zhang A: Enhanced glycolysis, regulated by HIF-1α via MCT-4, promotes inflammation in arsenite-induced carcinogenesis. Carcinogenesis. 38:615–626. 2017. View Article : Google Scholar : PubMed/NCBI | |
Tan FH, Bai Y, Saintigny P and Darido C: mTOR signalling in head and neck cancer: Heads up. Cells. 8:3332019. View Article : Google Scholar : | |
Jewell JL and Guan KL: Nutrient signaling to mTOR and cell growth. Trends Biochem Sci. 38:233–242. 2013. View Article : Google Scholar : PubMed/NCBI | |
Martelli AM, Buontempo F and McCubrey JA: Drug discovery targeting the mTOR pathway. Clin Sci (Lond). 132:543–568. 2018. View Article : Google Scholar | |
Liberti MV and Locasale JW: The Warburg effect: How does it benefit cancer cells? Trends Biochem Sci. 41:211–218. 2016. View Article : Google Scholar : PubMed/NCBI |