Disulfiram/Copper induces Bak-mediated caspase-independent apoptosis in MCF-7 cells

Beini Sun; Yu Wang; Hongce Chen; Qialing Huang; Chunchun An; Qiuqiang Zhan; Xiaoping Wang; Tongsheng Chen

doi:10.1016/j.biocel.2024.106731

Disulfiram/Copper induces Bak-mediated caspase-independent apoptosis in MCF-7 cells

Int J Biochem Cell Biol. 2024 Dec 22:106731. doi: 10.1016/j.biocel.2024.106731. Online ahead of print.

Authors

Beini Sun¹, Yu Wang¹, Hongce Chen¹, Qialing Huang¹, Chunchun An¹, Qiuqiang Zhan², Xiaoping Wang³, Tongsheng Chen⁴

Affiliations

¹ MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
² Centre for Optical and Electromagnetic Research, Guangdong Engineering Research Centre of Optoelectronic Intelligent Information Perception, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510006, PR China.
³ Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China. Electronic address: txp2938@jnu.edu.cn.
⁴ MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China. Electronic address: chentsh@scnu.edu.cn.

PMID: 39719221
DOI: 10.1016/j.biocel.2024.106731

Abstract

Disulfiram (DSF) and copper (Cu²⁺) in combination exhibit powerful anti-cancer effect on a variety of cancer cell lines. Here, we found that DSF/Cu²⁺ facilitated the accumulation of intracellular reactive oxygen species (ROS), and induced ROS-dependent apoptosis accompanied by chromatin condensation and phosphatidylserine externalization in MCF-7 cells. DSF/Cu²⁺ caused caspase-independent apoptosis by promoting the AIF translocation from mitochondria to nucleus. Most importantly, the cytotoxicity of DSF/Cu²⁺ was markedly inhibited by knocking out AIF, suggesting the indispensability of AIF in DSF/Cu²⁺-induced apoptosis. The pro-apoptotic protein BAK instead of BAX was upregulated and activated upon DSF/Cu²⁺ treatment, and the BAK knockout cells exhibited high resistance to DSF/Cu²⁺, indicating the importance of BAK in DSF/Cu²⁺-induced apoptosis. Additionally, both co-immunoprecipitation and live-cell quantitative fluorescence resonance energy transfer (FRET) analysis revealed that DSF/Cu²⁺ unlocked the binding of MCL-1 to BAK, which resulted in subsequent BAK homo-oligomerization. Overall, our data demonstrate for the first time that DSF/Cu²⁺ unlocks the binding of MCL-1 to BAK, thus leading BAK oligomerization and subsequent AIF nucleus translocation to mediate caspase-independent apoptosis in MCF-7 cells.

Keywords: AIF; Apoptosis; Bak; Caspase-independent; Disulfiram/Copper.