Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Signal Transduct Target Ther. 2021 Jun 28;6(1):242. doi: 10.1038/s41392-021-00595-3.
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.
先前的研究表明，超氧阴离子可以在水相中介导并放大 LDH 催化的过氧化氢产生，但它的生理相关性尚不清楚。在这里，我们发现 LDHA 和 LDHB 都表现出产生过氧化氢的活性，这种活性可以通过从 HeLa 细胞和患者胆管癌细胞分离的线粒体产生的超氧阴离子显著增强。在敲除 LDHA 或 LDHB 后，Hela 或 4T1 癌细胞产生的过氧化氢明显减少。在 LDHA 敲除的 HeLa 细胞中重新表达 LDHA 部分恢复了过氧化氢的产生。在 HeLa 和 4T1 细胞中，LDHA 或 LDHB 敲除或 LDH 抑制剂 FX11 显著降低了线粒体电子传递链调节剂（antimycin、oligomycin、rotenone）、缺氧和药理学 ROS 诱导剂 piperlogumine (PL) 和苯乙基异硫氰酸酯 (PEITC) 诱导的 ROS 产生。此外，LDHA 或 LDHB 敲除的 HeLa 或 4T1 细胞形成的肿瘤比对照细胞形成的肿瘤具有明显较低的氧化状态。总之，我们提供了一种机制理解，即 LDH 与癌细胞中细胞内过氧化氢产生或氧化应激之间的联系，这种联系在体外和体内都存在。
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