BNIP3 as a Regulator of Cisplatin-Induced Apoptosis

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A. S. Gorbunova¹, T. V. Denisenko¹, M. A. Yapryntseva¹, A. D. Pivnyuk¹, T. A. Prikazchikova², V. G. Gogvadze^1,3, and B. Zhivotovsky^1,3a*

¹Faculty of Basic Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia

²Skolkovo Institute of Science and Technology, Center of Life Sciences, 121205 Moscow, Russia

³Institute of Environmental Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden

^* To whom correspondence should be addressed.

Received July 16, 2020; Revised August 27, 2020; Accepted August 28, 2020

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BNIP3 is a member of Bcl-2 protein family involved in regulation of various forms of cell death. However, its role in these processes remains unclear and varies depending on the type of cancer cells and environmental factors (pH, O₂ level, etc.). Here, the role of BNIP3 in apoptosis regulation in lung adenocarcinoma cells was investigated. The suppressed expression of BNIP3 caused inhibition of oxygen consumption and stimulated production of the mitochondrial reactive oxygen species, suggesting the role of BNIP3 in induction of mitochondrial dysfunction and its potential involvement in regulation of cell death. Indeed, cytochrome c release in the cells with BNIP3 knockout and knockdown was higher than in the wild-type (WT) upon apoptosis stimulation by cisplatin. Moreover, suppression of BNIP3 expression led to the increase in the caspase-3 activity and, as a consequence, accumulation of the apoptotic marker – p89 fragment of poly(ADP-ribose)-polymerase (PARP) – as compared to WT cells. Analysis of the SubG1 population by flow cytometry confirmed the elevated level of apoptosis in the BNIP3 knockout cells. Pretreatment with the antioxidant Trolox did not affect cell death, indicating that it was independent on reactive oxygen species. These data show that BNIP3 is involved in maintaining normal functioning of mitochondria and, as a result, can regulate the mitochondrial pathway of cell death.

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KEY WORDS: BNIP3, apoptosis, mitophagy, lung adenocarcinoma, cisplatin

DOI: 10.1134/S0006297920100120

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