Lactate Dehydrogenases Amplify Reactive Oxygen Species in Cancer Cells in Response to Oxidative Stimuli

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2021 Jun 28

PMID 34176927

Citations 33

Authors

Hao Wu

Yuqi Wang

Minfeng Ying

Chengmeng Jin

Jiangtao Li

Xun Hu

Affiliations

Soon will be listed here.

Abstract

Previous studies demonstrated that superoxide could initiate and amplify LDH-catalyzed hydrogen peroxide production in aqueous phase, but its physiological relevance is unknown. Here we showed that LDHA and LDHB both exhibited hydrogen peroxide-producing activity, which was significantly enhanced by the superoxide generated from the isolated mitochondria from HeLa cells and patients' cholangiocarcinoma specimen. After LDHA or LDHB were knocked out, hydrogen peroxide produced by Hela or 4T1 cancer cells were significantly reduced. Re-expression of LDHA in LDHA-knockout HeLa cells partially restored hydrogen peroxide production. In HeLa and 4T1 cells, LDHA or LDHB knockout or LDH inhibitor FX11 significantly decreased ROS induction by modulators of the mitochondrial electron transfer chain (antimycin, oligomycin, rotenone), hypoxia, and pharmacological ROS inducers piperlogumine (PL) and phenethyl isothiocyanate (PEITC). Moreover, the tumors formed by LDHA or LDHB knockout HeLa or 4T1 cells exhibited a significantly less oxidative state than those formed by control cells. Collectively, we provide a mechanistic understanding of a link between LDH and cellular hydrogen peroxide production or oxidative stress in cancer cells in vitro and in vivo.

Citing Articles

Targeting Metabolic Vulnerabilities to Combat Drug Resistance in Cancer Therapy.

Khan T, Nagarajan M, Kang I, Wu C, Wangpaichitr M J Pers Med. 2025; 15(2).

PMID: 39997327 PMC: 11856717. DOI: 10.3390/jpm15020050.

Lactate and lactylation in cancer.

Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y Signal Transduct Target Ther. 2025; 10(1):38.

PMID: 39934144 PMC: 11814237. DOI: 10.1038/s41392-024-02082-x.

NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.

Niu K, Chen Z, Li M, Ma G, Deng Y, Zhang J Redox Biol. 2025; 79():103479.

PMID: 39742570 PMC: 11750563. DOI: 10.1016/j.redox.2024.103479.

Transcriptome and Proteome Analyses Revealed Differences in JEV-Infected PK-15 Cells in Response to Ferroptosis Agonists and Antagonists.

Zhou X, Chen Y, Kang X, Zhao A, Yang S Animals (Basel). 2024; 14(23).

PMID: 39682481 PMC: 11640317. DOI: 10.3390/ani14233516.

Crosstalk between lactate and tumor-associated immune cells: clinical relevance and insight.

Sun K, Shen Y, Xiao X, Xu H, Zhang Q, Li M Front Oncol. 2024; 14:1506849.

PMID: 39678492 PMC: 11638036. DOI: 10.3389/fonc.2024.1506849.

References

Iommarini L, Porcelli A, Gasparre G, Kurelac I . Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer. Front Oncol. 2017; 7:286. PMC: 5711814. DOI: 10.3389/fonc.2017.00286. View

Usatyuk P, Natarajan V . Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells. J Biol Chem. 2003; 279(12):11789-97. DOI: 10.1074/jbc.M311184200. View

Lennicke C, Rahn J, Lichtenfels R, Wessjohann L, Seliger B . Hydrogen peroxide - production, fate and role in redox signaling of tumor cells. Cell Commun Signal. 2015; 13:39. PMC: 4570748. DOI: 10.1186/s12964-015-0118-6. View

Chan P, Bielski B . Enzyme-catalyzed free radical reactions with nicotinamide adenine nucleotides. II. Lactate dehydrogenase-catalyzed oxidation of reduced nicotinamide adenine dinucleotide by superoxide radicals generated by xanthine oxidase. J Biol Chem. 1974; 249(4):1317-9. View

Orr A, Quinlan C, Perevoshchikova I, Brand M . A refined analysis of superoxide production by mitochondrial sn-glycerol 3-phosphate dehydrogenase. J Biol Chem. 2012; 287(51):42921-35. PMC: 3522288. DOI: 10.1074/jbc.M112.397828. View

Guzy R, Hoyos B, Robin E, Chen H, Liu L, Mansfield K . Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 2005; 1(6):401-8. DOI: 10.1016/j.cmet.2005.05.001. View

Koukourakis M, Giatromanolaki A, Winter S, Leek R, Sivridis E, Harris A . Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology. 2009; 77(5):285-92. DOI: 10.1159/000259260. View

Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H . Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell. 2006; 10(3):241-52. DOI: 10.1016/j.ccr.2006.08.009. View

Movafagh S, Crook S, Vo K . Regulation of hypoxia-inducible factor-1a by reactive oxygen species: new developments in an old debate. J Cell Biochem. 2014; 116(5):696-703. DOI: 10.1002/jcb.25074. View

10.

Berka V, Wu G, Yeh H, Palmer G, Tsai A . Three different oxygen-induced radical species in endothelial nitric-oxide synthase oxygenase domain under regulation by L-arginine and tetrahydrobiopterin. J Biol Chem. 2004; 279(31):32243-51. DOI: 10.1074/jbc.M404044200. View

11.

Lisanti M, Martinez-Outschoorn U, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell R . Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs "fertilizer". Cell Cycle. 2011; 10(15):2440-9. PMC: 3180186. DOI: 10.4161/cc.10.15.16870. View

12.

Rogatzki M, Ferguson B, Goodwin M, Gladden L . Lactate is always the end product of glycolysis. Front Neurosci. 2015; 9:22. PMC: 4343186. DOI: 10.3389/fnins.2015.00022. View

13.

Gewirtz D . A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999; 57(7):727-41. DOI: 10.1016/s0006-2952(98)00307-4. View

14.

Iwata S, Lee J, Okada K, Lee J, Iwata M, Rasmussen B . Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science. 1998; 281(5373):64-71. DOI: 10.1126/science.281.5373.64. View

15.

Pulaski B, Ostrand-Rosenberg S . Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res. 1998; 58(7):1486-93. View

16.

Leiblich A, Cross S, Catto J, Phillips J, Leung H, Hamdy F . Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene. 2006; 25(20):2953-60. DOI: 10.1038/sj.onc.1209262. View

17.

Kaminski P, Wolin M . Lactate and PO2 modulate superoxide anion production in bovine cardiac myocytes: potential role of NADH oxidase. Circulation. 1997; 96(2):614-20. DOI: 10.1161/01.cir.96.2.614. View

18.

Muller F, Liu Y, Van Remmen H . Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 2004; 279(47):49064-73. DOI: 10.1074/jbc.M407715200. View

19.

Raj L, Ide T, Gurkar A, Foley M, Schenone M, Li X . Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature. 2011; 475(7355):231-4. PMC: 3316487. DOI: 10.1038/nature10167. View

20.

Sun F, Dai C, Xie J, Hu X . Biochemical issues in estimation of cytosolic free NAD/NADH ratio. PLoS One. 2012; 7(5):e34525. PMC: 3343042. DOI: 10.1371/journal.pone.0034525. View