Chen Yan, Xia Chengxing, Ye Chunwei, Liu Feineng, Ou Yitian, Yan Ruping, Wang Haifeng, Yang Delin
Department of Urology, The Second Affiliated Hospital of Kunming Medical University, 374 Burma Avenue, Kunming 650101, China.
Open Life Sci. 2022 Jul 8;17(1):710-725. doi: 10.1515/biol-2022-0082. eCollection 2022.
Bladder cancer (BC) is one of the most common malignancies involving the urinary system. Our previous study demonstrated that cobra venom membrane toxin 12 (MT-12) could effectively inhibit BC cell growth and metastasis and induce apoptosis. However, the specific molecular mechanism remains unknown. In this study, we explored whether MT-12 inhibits BC cell proliferation by inducing autophagy cell death through mitochondrial dysfunction. As a result, MT-12 inhibited proliferation and colony formation in RT4 and T24 cells. In the BC xenograft mouse model, autophagy inhibitor 3-MA alleviated the inhibitory effect of MT-12 on tumor growth. In addition, immunostaining revealed downregulated autophagy in MT-12-treated RT4 and T24 cells. We also found that MT-12 led to dysfunctional mitochondria with decreased mitochondrial membrane potential, mtDNA abundance, and increased ROS production, ultimately inducing autophagic apoptosis the ROS/JNK/P53 pathway. MT-12 inhibits BC proliferation and by enhancing autophagy. MT-12 induces mitochondrial dysfunction and decreases autophagy, leading to increased ROS production, which in turn activates the JNK/p53 pathway, leading to BC apoptosis.
膀胱癌（BC）是泌尿系统最常见的恶性肿瘤之一。我们之前的研究表明，眼镜蛇毒膜毒素12（MT - 12）能有效抑制膀胱癌细胞的生长和转移并诱导其凋亡。然而，具体的分子机制仍不清楚。在本研究中，我们探讨了MT - 12是否通过线粒体功能障碍诱导自噬性细胞死亡来抑制膀胱癌细胞增殖。结果显示，MT - 12抑制了RT4和T24细胞的增殖及集落形成。在膀胱癌异种移植小鼠模型中，自噬抑制剂3 - MA减轻了MT - 12对肿瘤生长的抑制作用。此外，免疫染色显示经MT - 12处理的RT4和T24细胞中自噬下调。我们还发现，MT - 12导致线粒体功能障碍，线粒体膜电位、线粒体DNA丰度降低，活性氧生成增加，最终通过ROS/JNK/P53途径诱导自噬性凋亡。MT - 12通过增强自噬抑制膀胱癌细胞增殖。MT - 12诱导线粒体功能障碍并减少自噬，导致活性氧生成增加，进而激活JNK/p53途径，导致膀胱癌细胞凋亡。
