Current problems and thinkings on the cancer metabolic modulation therapy
SUN Xue-hua， ZHOU Fu-xiang
Department of Radiation and Medical Oncology， Zhongnan Hospital， Wuhan University/Key Laboratory of Tumor Biology Behavior of Hubei Province/Clinical Cancer Study Center of Hubei Province， Wuhan 430071， Hubei， China
Abstract：With advances in the research on cancer metabolic modulation therapy， it has been found that metabolic reprogramming of cancer cells with a single Warburg effect may not be representative of globally defined tumor metabolic reprogramming. At the same time， mitochondria play an important role in tumor metabolic reprogramming. Based on previous studies， we conclude that mitochondrial dysfunction can regulate tumor metabolic reprogramming through three modes: mitochondrial dysfunction-induced metabolic reprogramming， nuclear gene mutation-induced metabolic reprogramming， and mixed factors-induced metabolic reprogramming. Metabolic reprogramming of tumor cells is characterized by flexible metabolic plasticity due to differences in tumor genotype，tumor subtype， degree of differentiation， and changes of tumor microenvironment. Cancer cells can steal the metabolic wastes of tumor-related cells， and they are interdependent and interact with each other， showing the characteristics of metabolic symbiosis. In addition， cancer cells can also exhibit a stable heterozygous metabolic phenotype which affects the biological behavior of the tumor. This review begins with the current knowledge of tumor glucose regulation therapy， involves the current research problems， and summarizes the effects of mitochondrial dysfunction on metabolic reprogramming. It focuses on the metabolic plasticity of cancer cells， the metabolic coupling between tumor cells and tumor-associated cells， and the heterozygous metabolic phenotype of tumor cells. The effects of glycolysis and mitochondrial oxidative phosphorylation on the complexity of tumor metabolism are discussed， and the corresponding countermeasures are put forward for the complex tumor glucose metabolism.
孙雪花，周福祥. 当前肿瘤代谢调节治疗面临的问题及思考[J]. 肿瘤代谢与营养电子杂志, 2019, 6(3): 287-294.
SUN Xue-hua， ZHOU Fu-xiang. Current problems and thinkings on the cancer metabolic modulation therapy. Electron J Metab Nutr Cancer, 2019, 6(3): 287-294.
1.Hanahan D， Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
2.WARBURG O. On the origin of cancer cells. Science. 1956;123(3191):309-314.
3.WARBURG O. On respiratory impairment in cancer cells. Science. 1956;124(3215):269-270.
4.Zielonka J， Kalyanaraman B. “ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis”--a critical commentary. Free Radic Biol Med. 2008;45(9):1217-1219.
5.Cruz-Bermudez A， Laza-Briviesca R， Vicente-Blanco RJ， et al. Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1alpha in NSCLC which can be overcome by OXPHOS inhibition. Free Radic Biol Med. 2019;135:167-181.
6.Dang CV， Koppenol WH， Bounds PL. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325-337.
7.cGuppy M， Leedman P， Zu X， et al. Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002;364(Pt 1):309-315.
8.Vousden KH， Ryan KM. P53 and metabolism. Nat Rev Cancer. 2009;9(10):691-700.
9.King MP， Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989;246(4929):500-503.
10.Ishikawa K， Takenaga K， Akimoto M， et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science. 2008;320(5876):661-664.
11.Rensvold JW， Ong SE， Jeevananthan A， et al. Complementary RNA and protein profiling identifies iron as a key regulator of mitochondrial biogenesis. Cell Rep. 2013;3(1):237-245.
12.Jia D， Park JH， Jung KH， et al. Elucidating the metabolic plasticity of cancer: mitochondrial reprogramming and hybrid metabolic states. Cell. 2018;7(3):21.
13.Vidali S， Aminzadeh S， Lambert B， et al. Mitochondria: the ketogenic diet--a metabolism-based therapy. Int J Biochem Cell Biol. 2015;63:55-59.
14.Santos JG， Da CW， Schonthal AH， et al. Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma. Oncol Lett. 2018;15(1):1263-1270.
15.Zahra A， Fath MA， Opat E， et al. Consuming a ketogenic diet while receiving radiation and chemotherapy for locally advanced lung cancer and pancreatic cancer: the university of iowa experience of two phase 1 clinical trials. Radiat Res. 2017;187(6):743-754.
16.Zhang J， Jia PP， Liu QL， et al. Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo. J Lipid Res. 2018;59(4):625-634.
17.Griss T， Vincent EE， Egnatchik R， et al. Metformin antagonizes cancer cell proliferation by suppressing Mitochondrial-Dependent biosynthesis. PLoS Biol. 2015;13(12):e1002309.
18.Wu D， Hu D， Chen H， et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 2018;559(7715):637-641.
19.Gui DY， Sullivan LB， Luengo A， et al. Environment dictates dependence on mitochondrial complex i for NAD+ and aspartate production and determines cancer cell sensitivity to metformin. Cell Metab. 2016;24(5):716-727.
20.Li L， Wang L， Li J， et al. Metformin-Induced reduction of CD39 and CD73 blocks Myeloid-Derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 2018;78(7):1779-1791.
21.Zhang H， Guo X. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemoth Pharm. 2016;78(1):13-26.
22.Kordes S， Pollak MN， Zwinderman AH， et al. Metformin in patients with advanced pancreatic cancer: a double-blind， randomised， placebo-controlled phase 2 trial. Lancet Oncol. 2015;16(7):839-847.
23.Nayak A， Kapur A， Barroilhet L， et al. Oxidative phosphorylation: a target for novel therapeutic strategies against ovarian cancer. Cancers. 2018;10(9):337.
24.Pastò A， Bellio C， Pilotto G， et al. Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation， and resist glucose deprivation. Oncotarget. 2014;5(12):4305.
25.Zhou Y， Zhou Y， Shingu T， et al. Metabolic alterations in highly tumorigenic glioblastoma cells: preference for hypoxia and high dependency on glycolysis. J Biol Chem. 2011;286(37):32843-32853.
26.Vlashi E， Lagadec C， Vergnes L， et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci U S A. 2011;108(38):16062-16067.
27.Nakano I. Therapeutic potential of targeting glucose metabolism in glioma stem cells. Expert Opin Ther Targets. 2014;18(11):1233-1236.
28.Matassa DS， Amoroso MR， Lu H， et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ. 2016;23(9):1542-1554.
29.Yuneva MO， Fan TWM， Allen TD， et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 2012;15(2):157-170.
30.Pelicano H， Zhang W， Liu J， et al. Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Res. 2014;16(5):434.
31.Anderson AS， Roberts PC， Frisard MI， et al. Metabolic changes during ovarian cancer progression as targets for sphingosine treatment. Exp Cell Res. 2013;319(10):1431-1442.
32.Anderson AS， Roberts PC， Frisard MI， et al. Ovarian tumor-initiating cells display a flexible metabolism. Exp Cell Res. 2014;328(1):44-57.
33.Elia I， Schmieder R， Christen S， et al. Organ-specific cancer metabolism and its potential for therapy. Handb Exp Pharmacol. 2016;233(321):53.
34.Smolkova K， Plecita-Hlavata L， Bellance N， et al. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol. 2011;43(7):950-968.
35.LeBleu VS， O’Connell JT， Gonzalez HK， et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16(10):992-1003，1-15.
36.Justus CR， Sanderlin EJ， Yang LV. Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci. 2015;16(5):11055-11086.
37.Rossignol R， Gilkerson R， Aggeler R， et al. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 2004;64(3):985-993.
38.Faubert B， Li KY， Cai L， et al. Lactate metabolism in human lung tumors. Cell. 2017;171(2):358-371.
39.Hui S， Ghergurovich JM， Morscher RJ， et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017;551(7678):115-118.
40.Martinez-Outschoorn UE， Pestell RG， Howell A， et al. Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells. Cell Cycle. 2011;10(24):4208-4216.
41.Martinez-Outschoorn UE， Balliet RM， Rivadeneira DB， et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: a new paradigm for understanding tumor metabolism， the field effect and genomic instability in cancer cells. Cell Cycle. 2010;9(16):3256-3276.
42.Bonuccelli G， Whitaker-Menezes D， Castello-Cros R， et al. The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle. 2010;9(10):1960-1971.
43.Pavlides S， Whitaker-Menezes D， Castello-Cros R， et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009;8(23):3984-4001.
44.Balaban S， Shearer RF， Lee LS， et al. Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration. Cancer Metab. 2017;5:1.
45.Liang C， Qin Y， Zhang B， et al. Energy sources identify metabolic phenotypes in pancreatic cancer. Acta Biochim Biophys Sin (Shanghai). 2016;48(11):969-979.
46.Sonveaux P， Vegran F， Schroeder T， et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118(12):3930-3942.
47.Dalva-Aydemir S， Bajpai R， Martinez M， et al. Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin. Clin Cancer Res. 2015;21(5):1161-1171.
48.Lamari F， La Schiazza R， Guillevin R， et al. Biochemical exploration of energetic metabolism and oxidative stress in low grade gliomas: central and peripheral tumor tissue analysis. Ann Biol Clin (Paris)，2008;66(2):143-150.
49.Kim S， Kim DH， Jung WH， et al. Metabolic phenotypes in triple-negative breast cancer. Tumour Biol. 2013;34(3):1699-1712.
50.Yu L， Lu M， Jia D， et al. Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res. 2017;77(7):1564-1574.
51.Porporato PE， Payen VL， Perez-Escuredo J， et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 2014;8(3):754-766.
52.Park JH， Vithayathil S， Kumar S， et al. Fatty acid Oxidation-Driven src links mitochondrial energy reprogramming and oncogenic properties in Triple-Negative breast cancer. Cell Rep. 2016;14(9):2154-2165.
53.Telang S， Lane AN， Nelson KK， et al. The oncoprotein H-RasV12 increases mitochondrial metabolism. Mol Cancer. 2007;6:77.
54.Sancho P， Burgos-Ramos E， Tavera A， et al. MYC/PGC-1alpha balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab. 2015;22(4):590-605.
55.Cheong JH， Park ES，Liang J， et al. Dual inhibition of tumor energy pathway by 2-deoxy glucose and metformin is effective against a broad spectrum ofpreclinical cancer models. Mol Cancer Ther. 2011;10(12):2350-2362.
56.Elgendy M， Ciro M， Hosseini A， et al. Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3beta-MCL-1 axis. Cancer Cell. 2019;35(5):798-815.
57.Zhao Y， Butler EB， Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013;4:e532.
