BNIP3 contributes to silibinin-induced DNA double strand breaks in glioma cells via inhibition of mTOR

• Published in: Biochemical and biophysical research communications 2022-01, Vol.589, p.1-8
• Main Authors: Hua, Cong, Wang, Xuanzhong, Liang, Shipeng, chen, Xi, Li, Chen, You, Guangqiang, Wang, Chongcheng, Luo, Tianfei, Wang, Zhenchuan, Ge, Pengfei
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System y+ - metabolism; BNIP3; Catalase - metabolism; Cell Line, Tumor; Cysteine - metabolism; DNA Breaks, Double-Stranded - drug effects; DNA double Strand breaks; Down-Regulation - drug effects; Glioma - metabolism; Glioma - pathology; Glutathione - metabolism; Humans; Membrane Proteins - metabolism; mTOR; Proto-Oncogene Proteins - metabolism; Reactive Oxygen Species - metabolism; ROS; Silibinin; Silybin - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.11.110

BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR. [Display omitted] •BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS.•BNIP3 promotes silibinin-triggered ROS via downregulation of catalase.•BNIP3 enhances silibinin-triggered ROS by downregulating xCT and depleting GSH and cysteine.•BNIP3 exacerbates silibinin-induced downregulation of catalase and xCT via inhibition of mTOR.