Abstract
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 Buxus microphylla, 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
Highlights
Lung cancer is one of the most common malignant tumors and a frequent cause of death worldwide [1,2]
Cell cycle regulation plays a key role in antitumor therapy, and we tested whether Cyclovirobuxine D (CVB-D) treatment can induce cell-cycle arrest in lung cancer cells
Consistent with previous reports that CDC2 (CDK1) and cyclinB1 (CCNB1) are crucial to G2/M transition [27,28], CVB-D-induced G2/M arrest was confirmed by the decrease in G2/M-transition-related protein CDC2 and cyclin B1 in a dose-dependent manner in all lung cancer cells (Figure 1F)
Summary
Lung cancer is one of the most common malignant tumors and a frequent cause of death worldwide [1,2]. Parkin is an E3 ubiquitin ligase recruited by Pink, which translocates to mitochondria to mediate mitophagy initiation [15] Both BNIP3 (BCL2 and adenovirus E1B 19-kDa-interacting protein 3) and BNIP3L ( known as NIX) are localized to mitochondria and are atypical BH3-only members of the BCL2 family [16]. We demonstrated that CVB-D-induced lung-cancer cell death is closely associated with mitophagy activation. Mitophagy induced by CVB-D leads to a further increase of apoptotic death in lung cancer cells. These findings provide a cross link between mitophagy and apoptosis upon CVB-D treatment, which indicates that CVB-D is a potential candidate and is of particular clinical relevance for lung-cancer treatment
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