Beijing International Science and Technology Cooperation Base of Antivirus Drug, Department of Biology, Faculty of Environment and Life, Beijing University of Technology, Beijing, China.
Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing, China.
FEBS Open Bio. 2023 Aug;13(8):1522-1535. doi: 10.1002/2211-5463.13666. Epub 2023 Jul 8.
Oncogene E6 plays a critical role in the development and progression of esophageal cancer caused by human papillomavirus (HPV) infection. Alpha-ketoglutarate (AKG) is a key metabolite in the tricarboxylic acid cycle and has been widely used as a dietary and anti-ageing supplement. In this study, we found that treating esophageal squamous carcinoma cells with a high dose of AKG can induce cell pyroptosis. Furthermore, our research confirms that HPV18 E6 inhibits AKG-induced pyroptosis of esophageal squamous carcinoma cells by lowering P53 expression. P53 downregulates malate dehydrogenase 1 (MDH1) expression; however, MDH1 downregulates L-2-hydroxyglutarate (L-2HG) expression, which inhibits a rise in reactive oxygen species (ROS) levels-as L-2HG is responsible for excessive ROS. This study reveals the actuating mechanism behind cell pyroptosis of esophageal squamous carcinoma cells induced by high concentrations of AKG, and we posit the molecular pathway via which the HPV E6 oncoprotein inhibits cell pyroptosis.
癌基因 E6 在人乳头瘤病毒（HPV）感染引起的食管癌的发生和发展中起着关键作用。α-酮戊二酸（AKG）是三羧酸循环中的关键代谢物，已广泛用作膳食和抗衰老补充剂。在这项研究中，我们发现用高剂量 AKG 处理食管鳞状癌细胞可诱导细胞焦亡。此外，我们的研究证实 HPV18 E6 通过降低 P53 表达来抑制 AKG 诱导的食管鳞状癌细胞焦亡。P53 下调苹果酸脱氢酶 1（MDH1）的表达；然而，MDH1 下调 L-2-羟戊二酸（L-2HG）的表达，抑制活性氧（ROS）水平的升高——因为 L-2HG 负责过多的 ROS。本研究揭示了高浓度 AKG 诱导的食管鳞状癌细胞细胞焦亡的作用机制，并提出了 HPV E6 癌蛋白抑制细胞焦亡的分子途径。
