Research Paper Volume 13, Issue 9 pp 12955—12972
PINK1/Parkin-mediated mitophagy inhibits warangalone-induced mitochondrial apoptosis in breast cancer cells
- 1 Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, Guangdong, China
- 2 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
- 3 The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, Guangdong, China
Received: October 28, 2020 Accepted: January 14, 2021 Published: April 30, 2021
https://doi.org/10.18632/aging.202965How to Cite
Abstract
Breast cancer is the most common malignancy in women all around the world, especially in many countries in Asia. However, antitumor drugs with unique curative effects and low toxic side-effects have not been found yet. Warangalone is an isoflavone extracted from the Cudrania tricuspidata fruit, and is reported to possess anti-inflammatory and anti-cancer activity. The purpose of this study was to determine the effects of warangalone on breast cancer cells. In this study, we found that warangalone decreased the viability of breast cancer cells by increasing the generation of reactive oxygen species (ROS) resulting in mitochondrial damage and decreased mitochondrial membrane potential (MMP). Warangalone induced mitochondrial apoptosis by increasing the BAX/BCL-2 ratio. Warangalone activated mitophagy via upregulation of PINK1 and Parkin expression and co-localization. The combination of warangalone and autophagy inhibitors or PINK1 siRNA increased the degree of cell apoptosis compared to treatment with warangalone alone. Warangalone damages mitochondria via ROS, thereby triggering PINK1/Parkin-mediated mitophagy and inducing mitochondrial apoptosis. However, autophagy/mitophagy protects against warangalone-induced mitochondrial apoptosis. A combination of warangalone and autophagy/mitophagy inhibitors may be a potential treatment for breast cancer.
Abbreviations
3-MA: 3-methyladenine; Carr: cudrania tricuspidata; CLSM: confocal laser scanning microscope; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DCFH-DA: dichlorodihydrofluorescein diacetate; DMEM: Dulbecco's modified Eagle’s medium; ER: estrogen receptor; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HER2: human epidermal growth factor receptor 2; LC3: microtubule-associated protein 1 light chain 3; MDC: monodansylcadaverine; MMP: mitochondrial membrane potential; MTT: 3-(4,5-dimethyl-2-thia-zolyl)-2,5-diphenyl-2-H-tetrazolium bromide; NAC: N-acetyl-L-cysteine; PARP: poly-ADP-ribose polymerase; PBS: phosphate-buffered saline; PCD: programmed cell death; PI: propidine iodide; PINK1: PTEN-induced putative kinase 1; PR: progesterone receptor; ROS: reactive oxygen species; siRNA: small interfering RNA; TEM: transmission electron microscope; TNBC: triple-negative breast cancer.