School of Life Sciences, Chongqing University, Chongqing 401331, China.
Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Department of Pharmacology, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518055, China.
Int J Mol Sci. 2021 May 29;22(11):5820. doi: 10.3390/ijms22115820.
Mitophagy plays a pro-survival or pro-death role that is cellular-context- and stress-condition-dependent. In this study, we revealed that cyclovirobuxine D (CVB-D), a natural compound derived from , was able to provoke mitophagy in lung cancer cells. CVB-D-induced mitophagy potentiates apoptosis by promoting mitochondrial dysfunction. Mechanistically, CVB-D initiates mitophagy by enhancing the expression of the mitophagy receptor BNIP3 and strengthening its interaction with LC3 to provoke mitophagy. Our results further showed that p65, a transcriptional suppressor of BNIP3, is downregulated upon CVB-D treatment. The ectopic expression of p65 inhibits BNIP3 expression, while its knockdown significantly abolishes its transcriptional repression on BNIP3 upon CVB-D treatment. Importantly, nude mice bearing subcutaneous xenograft tumors presented retarded growth upon CVB-D treatment. Overall, we demonstrated that CVB-D treatment can provoke mitophagy and further revealed that the p65/BNIP3/LC3 axis is one potential mechanism involved in CVB-D-induced mitophagy in lung cancer cells, thus providing an effective antitumor therapeutic strategy for the treatment of lung cancer patients.
线粒体自噬在细胞环境和应激条件依赖的情况下发挥着促进生存或促进死亡的作用。在这项研究中,我们揭示了环维黄杨星 D(CVB-D),一种来源于 的天然化合物,能够在肺癌细胞中引发线粒体自噬。CVB-D 诱导的线粒体自噬通过促进线粒体功能障碍增强细胞凋亡。在机制上,CVB-D 通过增强线粒体自噬受体 BNIP3 的表达并加强其与 LC3 的相互作用来引发线粒体自噬。我们的结果进一步表明,p65 是 BNIP3 的转录抑制因子,在 CVB-D 处理后表达下调。p65 的异位表达抑制 BNIP3 的表达,而其敲低则显著消除了 p65 在 CVB-D 处理后对 BNIP3 的转录抑制作用。重要的是,携带皮下异种移植肿瘤的裸鼠在 CVB-D 处理后肿瘤生长减缓。总的来说,我们证明了 CVB-D 处理可以引发线粒体自噬,并进一步揭示了 p65/BNIP3/LC3 轴是 CVB-D 诱导肺癌细胞线粒体自噬的潜在机制之一,从而为治疗肺癌患者提供了一种有效的抗肿瘤治疗策略。