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.
Highlights
Hydrogen peroxide (H2O2) plays important roles in cancer initiation and development,[1,2] but the molecular mechanism underlying H2O2 production in cancer cells is not completely understood
The results suggest that without agents interfering with ETC, LDHs inhibit ROS production, agreeable with previous reports[27,28,32]; with agents interfering with ETC, LDH enhances ROS production, consistent with our observations on the in vitro enzyme assays (Fig. 1a–f), H2O2producing activity of LDH enhanced by mitochondria (Fig. 1g, j, k), H2O2 production by cells with or without LDH knockout (Fig. 2c, i), and HeLa/ρ0 cells (Fig. 3)
Increased H2O2 production is a characteristics of cancer cells,[1,2] but the underlying mechanism is not completely understood
Summary
Hydrogen peroxide (H2O2) plays important roles in cancer initiation and development,[1,2] but the molecular mechanism underlying H2O2 production in cancer cells is not completely understood. In one cycle of the reactions, one molecule of H2O2 is generated and the molecule of superoxide is recycled it can initiate another cycle of the above reaction. One molecule of superoxide can initiate many round reactions, leading to generation of many molecules of H2O2. These studies build solid theoretical basis for LDH-involved H2O2 production, it has not attracted much attention since . Up to date, it is unclear if LDH-catalyzed production of H2O2 is physiologically relevant. LDH-catalyzed H2O2 production should present in cancer cells, on the following basis. It is estimated that about 0.12–2% of respiration in the mitochondria is converted to superoxide in vitro, and less in vivo.[6]
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