A Review of the Redox Regulation of Tumor Metabolism

WANG Kui, MING Hui, ZUO Jing, TIAN Hai-long, HUANG Can-hua


Metabolic aberrance is one of the hallmarks of cancer. The metabolic patterns in cancer cells are well reprogrammed to provide building blocks and energy for their sustained growth. During tumor metabolic reprogramming, reactive oxygen species (ROS) are generated and the antioxidant systems are activated. High levels of ROS lead to oxidative damage and even cell death, whereas ROS at low levels act as second messenger to regulate many signaling pathways. Recently, with the revisiting of oxidative stress, it has been found that ROS can directly mediate the redox modifications of proteins, resulting in protein conformational and functional alterations. However, only a very small portion of metabolic enzymes, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and PKM2, etc., has been reported to undergo redox modifications. Whether other metabolic enzymes are regulated by redox modifications and thus exhibit critical functions remain largely unknown. Moreover, the specific spatio-temporal targeting of redox modifications of metabolic enzymes, as well as overcoming the existed redox and metabolic adaptation, are key points to be solved. Here, we will review the reported redox modification patterns of metabolic enzymes, the involved regulatory mechanisms and their roles in tumorigenesis and tumor progress. In addition, we will discuss the future therapeutic strategies targeting redox modifications of metabolic enzymes for tumor treatment.


Keywords: Tumor metabolism, Reactive oxygen species, Oxidative stress, Redox modifications, Tumor therapy


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WARBURG O, WIND F, NEGELEIN E. The metabolism of tumors in the body. J Gen Physiol,1927,8(6): 519–530.

VERNIERI C, CASOLA S, FOIANI M, et al. Targeting cancer metabolism: dietary and pharmacologic interventions. Cancer Discov, 2016,6(12): 1315–1333.

WANG C, HE C, LU S, et al. Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF. Cell Death Dis,2020, 11(8): 1–16.

HAUGRUD A B, ZHUANG Y, COPPOCK J D, et al. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat,2014,147(3): 539–550.

BERGAGGIO E, RIGANTI C, GARAFFO G, et al. IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood,2019,133(2): 156–167.

XIANG Y, STINE Z E, XIA J, et al. Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Invest,2015,125(6): 2293–2306.

YUAN L, SHENG X, CLARK L H, et al. Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer. Am J Transl Res,2016,8(10): 4265–4277.

JONES C L, STEVENS B M, D'ALESSANDRO A, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell,2018,34(5): 724–740.

CHENG S, WANG G, WANG Y, et al. Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer. Clin Sci,2019,133(15): 1745–1758.

LI L, JIANG Z, YAO Y, et al. (−)-Hydroxycitric acid regulates energy metabolism by activation of AMPK-PGC1α-NRF1 signal pathway in primary chicken hepatocytes. Life Sci, 2020, 254: 117785 [2020-04-20]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648812/. doi: 10.1038/s41467-017-01106-1.

SOSA V, MOLIN T, SOMOZA R, et al. Oxidative stress and cancer: an overview. Ageing Res Rev,2013,12(1): 376–390.

SIES H, JONES D P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol,2020,21(7): 363–383.

WANG K, JIANG J, LEI Y, et al. Targeting metabolic–redox circuits for cancer therapy. Trends Biochem Sci,2019,44(5): 401–414.

CLEMENTINO M, SHI X, ZHANG Z. Oxidative stress and metabolic reprogramming in Cr (Ⅵ) carcinogenesis. Curr Opin Toxicol,2018,8(1): 20–27.

SONG I K, LEE J J, CHO J H, et al. Degradation of redox-sensitive proteins including peroxiredoxins and DJ-1 is promoted by oxidation-induced conformational changes and ubiquitination. Sci Rep,2016,6(1): 1–15.

SMITH K A, WAYPA G B, SCHUMACKER P T. Redox signaling during hypoxia in mammalian cells. Redox Biol,2017,13(1): 228–234.

MOLDOGAZIEVA N T, LUTSENKO S V, TERENTIEV A A. Reactive oxygen and nitrogen species–induced protein modifications: implication in carcinogenesis and anticancer therapy. Cancer Res,2018,78(21): 6040–6047.

REN X, ZOU L, ZHANG X, et al. Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxid Redox Signal,2017,27(13): 989–1010.

BEGAS P, LIEDGENS L, MOSELER A, et al. Glutaredoxin catalysis requires two distinct glutathione interaction sites. Nat Commun,2017, 8(1): 1–13.

ELKO E A, CUNNIFF B, SEWARD D J, et al. Peroxiredoxins and beyond; redox systems regulating lung physiology and disease. Antioxid Redox Signal,2019,31(14): 1070–1091.

SHANMUGASUNDARAM K, NAYAK B, FRIEDRICHS W, et al. NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance. Nat Commun, 2017, 8(1): 997[2020-04-20]. https://www.nature.com/articles/s41467-017-01106-1. doi: 10.1038/s41467-017-01106-1.


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