Potential of electron transfer and its application in dictating routes of biochemical processes associated with metabolic reprogramming

Abstract

Metabolic reprogramming, such as abnormal utilization of glucose, addiction to glutamine, and increased de-novo lipid synthesis, extensively occurs in proliferating cancer cells, but the underneath rationale has remained to be elucidated. Based on the concept of the degree of reduction of a compound, we have recently proposed a calculation termed as potential of electron transfer (PET), which is used to characterize the degree of electron redistribution coupled with metabolic transformations. When this calculation is combined with the assumed model of electron balance in a cellular context, the enforced selective reprogramming could be predicted by examining the net changes of the PET values associated with the biochemical pathways in anaerobic metabolism. Some interesting properties of PET in cancer cells were also discussed, and the model was extended to uncover the chemical nature underlying aerobic glycolysis that essentially results from energy requirement and electron balance. Enabling electron transfer could drive metabolic reprogramming in cancer metabolism. Therefore, the concept and model established on electron transfer could guide the treatment strategies of tumors and future studies on cellular metabolism.

Keywords

metabolic reprogramming / potential of electron transfer / cell proliferation / aerobic glycolysis / cancer metabolism

References

[1] Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 1987; 235(4795): 1492–1495

[2] Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008; 105(48): 18782–18787

[3] Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 2010; 35(8): 427–433

[4] Sun C, Li T, Song X, Huang L, Zang Q, Xu J, Bi N, Jiao G, Hao Y, Chen Y, Zhang R, Luo Z, Li X, Wang L, Wang Z, Song Y, He J, Abliz Z. Spatially resolved metabolomics to discover tumor-associated metabolic alterations. Proc Natl Acad Sci USA 2019; 116(1): 52–57

[5] Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 2012; 336(6084): 1040–1044

[6] Zhu J, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol 2019; 20(7): 436–450

[7] Huang D, Li C, Zhang H. Hypoxia and cancer cell metabolism. Acta Biochim Biophys Sin (Shanghai) 2014; 46(3): 214–219

[8] Warburg O. On the origin of cancer cells. Science 1956; 123(3191): 309–314

[9] Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, Kremer D, Hwang RF, Witkiewicz AK, Ying H, Asara JM, Evans RM, Cantley LC, Lyssiotis CA, Kimmelman AC. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 2016; 536(7617): 479–483

[10] Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, Yuan C, Bao Y, Townsend MK, Tworoger SS, Davidson SM, Papagiannakopoulos T, Yang A, Dayton TL, Ogino S, Stampfer MJ, Giovannucci EL, Qian ZR, Rubinson DA, Ma J, Sesso HD, Gaziano JM, Cochrane BB, Liu S, Wactawski-Wende J, Manson JE, Pollak MN, Kimmelman AC, Souza A, Pierce K, Wang TJ, Gerszten RE, Fuchs CS, Vander Heiden MG, Wolpin BM. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 2014; 20(10): 1193–1198

[11] Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, Bai AHC, Karra D, Piro RM, Felsberg J, Addington A, Lemke D, Weibrecht I, Hovestadt V, Rolli CG, Campos B, Turcan S, Sturm D, Witt H, Chan TA, Herold-Mende C, Kemkemer R, König R, Schmidt K, Hull WE, Pfister SM, Jugold M, Hutson SM, Plass C, Okun JG, Reifenberger G, Lichter P, Radlwimmer B. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 2013; 19(7): 901–908

[12] Loayza-Puch F, Rooijers K, Buil LC, Zijlstra J, Oude Vrielink JF, Lopes R, Ugalde AP, van Breugel P, Hofland I, Wesseling J, van Tellingen O, Bex A, Agami R. Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature 2016; 530(7591): 490–494

[13] Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, Phang JM. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 2012; 109(23): 8983–8988

[14] Hollinshead KER, Munford H, Eales KL, Bardella C, Li C, Escribano-Gonzalez C, Thakker A, Nonnenmacher Y, Kluckova K, Jeeves M, Murren R, Cuozzo F, Ye D, Laurenti G, Zhu W, Hiller K, Hodson DJ, Hua W, Tomlinson IP, Ludwig C, Mao Y, Tennant DA. Oncogenic IDH1 mutations promote enhanced proline synthesis through PYCR1 to support the maintenance of mitochondrial redox homeostasis. Cell Rep 2018; 22(12): 3107–3114

[15] Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2012; 481(7381): 385–388

[16] Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012; 481(7381): 380–384

[17] Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA 2011; 108(49): 19611–19616

[18] Wang Y, Bai C, Ruan Y, Liu M, Chu Q, Qiu L, Yang C, Li B. Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia. Nat Commun 2019; 10(1): 201

[19] Gao X, Lin SH, Ren F, Li JT, Chen JJ, Yao CB, Yang HB, Jiang SX, Yan GQ, Wang D, Wang Y, Liu Y, Cai Z, Xu YY, Chen J, Yu W, Yang PY, Lei QY. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun 2016; 7(1): 11960

[20] Schug ZT, Vande Voorde J, Gottlieb E. The metabolic fate of acetate in cancer. Nat Rev Cancer 2016; 16(11): 708–717

[21] Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 2015; 27(1): 57–71

[22] Kamphorst JJ, Chung MK, Fan J, Rabinowitz JD. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer Metab 2014; 2(1): 23

[23] Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, Walters H, Tantawy MN, Fu A, Manning HC, Horton JD, Hammer RE, McKnight SL, Tu BP. Acetate dependence of tumors. Cell 2014; 159(7): 1591–1602

[24] Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol 2015; 17(4): 351–359

[25] Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23(1): 27–47

[26] Vazquez A, Kamphorst JJ, Markert EK, Schug ZT, Tardito S, Gottlieb E. Cancer metabolism at a glance. J Cell Sci 2016; 129(18): 3367–3373

[27] Liu M, Wang Y, Yang C, Ruan Y, Bai C, Chu Q, Cui Y, Chen C, Ying G, Li B. Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth. J Exp Med 2020; 217(3): e20191226

[28] Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 5th edition. New York: Garland Science, 2008

[29] Titov DV, Cracan V, Goodman RP, Peng J, Grabarek Z, Mootha VK. Complementation of mitochondrial electron transport chain by manipulation of the NAD⁺/NADH ratio. Science 2016; 352(6282): 231–235

[30] Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 2015; 162(3): 552–563

[31] Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 2015; 162(3): 540–551

[32] Mullen AR, Hu Z, Shi X, Jiang L, Boroughs LK, Kovacs Z, Boriack R, Rakheja D, Sullivan LB, Linehan WM, Chandel NS, DeBerardinis RJ. Oxidation of α-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep 2014; 7(5): 1679–1690

[33] Li M, Lu Y, Li Y, Tong L, Gu XC, Meng J, Zhu Y, Wu L, Feng M, Tian N, Zhang P, Xu T, Lin SH, Tong X. Transketolase deficiency protects the liver from DNA damage by increasing levels of ribose 5-phosphate and nucleotides. Cancer Res 2019; 79(14): 3689–3701

[34] Li Q, Qin T, Bi Z, Hong H, Ding L, Chen J, Wu W, Lin X, Fu W, Zheng F, Yao Y, Luo ML, Saw PE, Wulf GM, Xu X, Song E, Yao H, Hu H. Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer. Nat Commun 2020; 11(1): 1456

[35] Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, Maddocks OD. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 2014; 7(4): 1248–1258

[36] Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 2013; 493(7433): 542–546

[37] Gravel SP, Hulea L, Toban N, Birman E, Blouin MJ, Zakikhani M, Zhao Y, Topisirovic I, St-Pierre J, Pollak M. Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res 2014; 74(24): 7521–7533

[38] Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, Mackay GM, Labuschagne CF, Gay D, Kruiswijk F, Blagih J, Vincent DF, Campbell KJ, Ceteci F, Sansom OJ, Blyth K, Vousden KH. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 2017; 544(7650): 372–376

[39] Yang L, Garcia Canaveras JC, Chen Z, Wang L, Liang L, Jang C, Mayr JA, Zhang Z, Ghergurovich JM, Zhan L, Joshi S, Hu Z, McReynolds MR, Su X, White E, Morscher RJ, Rabinowitz JD. Serine catabolism feeds NADH when respiration is impaired. Cell Metab 2020; 31(4): 809–821.e6

[40] Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 2016; 41(3): 211–218

[41] Kilburn DG, Lilly MD, Webb FC. The energetics of mammalian cell growth. J Cell Sci 1969; 4(3): 645–654

[42] Slavov N, Budnik BA, Schwab D, Airoldi EM, van Oudenaarden A. Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis. Cell Rep 2014; 7(3): 705–714

[43] Luengo A, Li Z, Gui DY, Sullivan LB, Zagorulya M, Do BT, Ferreira R, Naamati A, Ali A, Lewis CA, Thomas CJ, Spranger S, Matheson NJ, Vander Heiden MG. Increased demand for NAD⁺ relative to ATP drives aerobic glycolysis. Mol Cell 2021; 81(4): 691–707.e6

[44] Epstein T, Xu L, Gillies RJ, Gatenby RA. Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane. Cancer Metab 2014; 2(1): 7

[45] Dai Z, Shestov AA, Lai L, Locasale JW. A flux balance of glucose metabolism clarifies the requirements of the Warburg effect. Biophys J 2016; 111(5): 1088–1100

[46] Shuler M, Kargi F, DeLisa M. Bioprocess Engineering: Basic Concepts. 3rd edition. Upper Saddle River, NJ: Prentice Hall, 2017

[47] Phang JM, Liu W, Hancock C, Christian KJ. The proline regulatory axis and cancer. Front Oncol 2012; 2: 60

[48] Berg JM, Tymoczko JL, Stryer L. Biochemistry. 7th edition. New York: W.H. Freeman, 2012

[49] Glenn K, Smith KS. Allosteric regulation of Lactobacillus plantarum xylulose 5-phosphate/fructose 6-phosphate phosphoketolase (Xfp). J Bacteriol 2015; 197(7): 1157–1163

[50] Tirinato L, Pagliari F, Limongi T, Marini M, Falqui A, Seco J, Candeloro P, Liberale C, Di Fabrizio E. An overview of lipid droplets in cancer and cancer stem cells. Stem Cells Int 2017; 2017: 1656053

[51] Liu Q, Luo Q, Halim A, Song G. Targeting lipid metabolism of cancer cells: a promising therapeutic strategy for cancer. Cancer Lett 2017; 401: 39–45

[52] Medes G, Thomas A, Weinhouse S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res 1953; 13(1): 27–29

[53] Ookhtens M, Kannan R, Lyon I, Baker N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol 1984; 247(1 Pt 2): R146–R153

[54] Balaban S, Nassar ZD, Zhang AY, Hosseini-Beheshti E, Centenera MM, Schreuder M, Lin HM, Aishah A, Varney B, Liu-Fu F, Lee LS, Nagarajan SR, Shearer RF, Hardie RA, Raftopulos NL, Kakani MS, Saunders DN, Holst J, Horvath LG, Butler LM, Hoy AJ. Extracellular fatty acids are the major contributor to lipid synthesis in prostate cancer. Mol Cancer Res 2019; 17(4): 949–962

[55] Garcia-Bermudez J, Baudrier L, Bayraktar EC, Shen Y, La K, Guarecuco R, Yucel B, Fiore D, Tavora B, Freinkman E, Chan SH, Lewis C, Min W, Inghirami G, Sabatini DM, Birsoy K. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 2019; 567(7746): 118–122

[56] Palm W, Thompson CB. Nutrient acquisition strategies of mammalian cells. Nature 2017; 546(7657): 234–242

[57] Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 2009; 461(7260): 109–113

[58] Buchheit CL, Weigel KJ, Schafer ZT. Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression. Nat Rev Cancer 2014; 14(9): 632–641

[59] Lee CK, Jeong SH, Jang C, Bae H, Kim YH, Park I, Kim SK, Koh GY. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation. Science 2019; 363(6427): 644–649

[60] Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 2013; 12(1): 152

[61] Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11(5): 325–337

[62] Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 2005; 8(4): 311–321

[63] Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, Lombardo PS, Van Nostrand JL, Hutchins A, Vera L, Gerken L, Greenwood J, Bhat S, Harriman G, Westlin WF, Harwood HJ Jr, Saghatelian A, Kapeller R, Metallo CM, Shaw RJ. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 2016; 22(10): 1108–1119

[64] Stine JE, Guo H, Sheng X, Han X, Schointuch MN, Gilliam TP, Gehrig PA, Zhou C, Bae-Jump VL. The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer. Oncotarget 2016; 7(1): 946–960

[65] Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 2017; 14(1): 11–31

[66] Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest 2013; 123(9): 3685–3692

[67] Sun RC, Denko NC. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 2014; 19(2): 285–292

[68] Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3(3): 177–185

[69] Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, King RJ, Abrego J, Goode GD, Dasgupta A, Illies AL, Gebregiworgis T, Dai B, Augustine JJ, Murthy D, Attri KS, Mashadova O, Grandgenett PM, Powers R, Ly QP, Lazenby AJ, Grem JL, Yu F, Matés JM, Asara JM, Kim JW, Hankins JH, Weekes C, Hollingsworth MA, Serkova NJ, Sasson AR, Fleming JB, Oliveto JM, Lyssiotis CA, Cantley LC, Berim L, Singh PK. MUC1 and HIF-1α signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell 2017; 32(1): 71–87.e7

[70] Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 2008; 68(4): 1003–1011

Acknowledgements

We would like to thank the members of Binghui Li’s Lab for their suggestions and discussions. This work is supported by Grants from the National Natural Science Foundation of China (No. 81972567 to Binghui Li and No. 81772843 to Guoguang Ying), and Start Grant from Advanced Innovation Center for Human Brain Protection (to Binghui Li).

Compliance with ethics guidelines

Ronghui Yang, Guoguang Ying, and Binghui Li declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2021 Higher Education Press