Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Abstract

These days, cancer can still not be effectively cured because cancer cells readily develop resistance to anticancer drugs. Therefore, an effective combination of drugs with different mechanisms to prevent drug resistance has become a very important issue. Furthermore, the BH3-only protein BNIP3 is involved in both apoptotic and autophagic cell death. In this study, lung cancer cells were treated with a chemotherapy drug alone or in combination to identify the role of BNIP3 and autophagy in combination chemotherapy for treating cancer. Our data revealed that various combinational treatments of two drugs could increase cancer cell death and cisplatin in combination with rapamycin or LBH589, which triggered the cell cycle arrest at the S phase. Cells with autophagosome and pEGFP-LC3 puncta increased when treated with drugs. To confirm the role of autophagy, cancer cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA). 3-MA sensitized cancer cells to chemotherapy drug treatments. These results suggest that autophagy may be responsible for cell survival in combination chemotherapy for lung cancer. Moreover, BNIP3 was induced and localized in mitochondria when cells were treated with drugs. The transfection of a dominant negative transmembrane deletion construct of BNIP3 (BNIP3ΔTM) and treatment of a reactive oxygen species (ROS) inhibitor suppressed chemo drug-induced cell death. These results indicate that BNIP3 and ROS may be involved in combination chemo drug-induced cell death. However, chemo drug-induced autophagy may protect cancer cells from drug cytotoxicity. As a result, inhibiting autophagy may improve the effects of combination chemotherapy when treating lung cancer. K E Y W O R D S autophagy, BNIP3, combination chemotherapy, reactive oxygen species How to cite this article: Chung L-Y, Tang S-J, Wu Y-C, et al. Platinum-based combination chemotherapy triggers cancer cell death through induction of Bnip3 and ROS, but not autophagy.

Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

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“…Oxidative stress was reported to promote the migration, invasion, and metastasis of NSCLC through the LATS2/YAP signaling pathway in a recent study [ 101 ]. Reactive oxygen species (ROS) are the downstream products of oxidative stress and have been identified to be involved in response to anti-cancer therapies in human NSCLC [ 102 , 103 ]. A previous study by Huang et al reported that the activation of YAP increased the accumulation of ROS by downregulating the antioxidant enzyme GPX2 in human lung squamous cell carcinoma [ 104 ].…”

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“…The development of chemical agents for BNIP3 targeting could be a prospective strategy to overcome radioresistance acquired during inoperable tumor therapy. In addition to autophagy, BNIP3 participates in cisplatin-induced cell death, including apoptosis [ 78 , 85 ]. Cisplatin treatment increases BNIP3 protein levels; however, its combination with hypoxia reduced BNIP3 in lung cancer cell lines.…”

“…The histone deacetylases inhibitor, panobinostat, LBH589, is a promising agent for lung cancer therapy through the impairment of histone deacetylation and subsequent weakening of gene transcription, especially oncogenes. The combination of LBH589 and cisplatin triggers BNIP3 insertion into the mitochondrial membrane by its TM domain, which eventually promotes ROS and potential mitochondrial membrane loss, leading to apoptotic cell death in the lungs [ 85 ]. The molecular design of drugs for the stimulation of BNIP3 TM domain insertion into mitochondria could provide an efficient tool to enhance sensitivity to apoptosis.…”