Alpha-mangostin induces apoptosis through activation of reactive oxygen species and ASK1/p38 signaling pathway in cervical cancer cells

// Chien-Hsing Lee 1, 2 , Tsung-Ho Ying 3, 4 , Hui-Ling Chiou 5 , Shu-Ching Hsieh 5 , Shiua-Hua Wen 6 , Ruey-Hwang Chou 7, 8, * and Yi-Hsien Hsieh 6, 9, 10, * 1 School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan 2 Division of Pediatric Surgery, Department of Surgery, China Medical University Children's Hospital, Taichung, Taiwan 3 Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan 4 Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan 5 School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan 6 Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan 7 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan 8 Department of Biotechnology, Asia University, Taichung, Taiwan 9 Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan 10 Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Ruey-Hwang Chou, email: rhchou@gmail.com Yi-Hsien Hsieh, email: hyhsien@csmu.edu.tw Keywords: α-mangostin, apoptosis, reactive oxygen species, p38MAPK, cervical cancer Received: November 02, 2016      Accepted: April 20, 2017      Published: May 07, 2017 ABSTRACT Alpha-mangostin, a natural xanthonoid, has been reported to possess the anti-cancer property in various types of human cancer. However, its effects and mechanism of α-mangostin in cervical cancer remain unclear. We found that α-mangostin effectively inhibited cell viability, resulted in loss of mitochondrial membrane potential (MMP), release of cytochrome C, increase of Bax, decrease of Bcl-2, and activation of caspase-9/caspase-3 cascade in cervical cancer cells. Alpha-mangostin elevated the contents of reactive oxygen species (ROS) to activate p38. Disrupting ASK1/p38 signaling pathway by a specific inhibitor of p38, or by the siRNAs against ASK1, MKK3/6, or p38, significantly abolished α-mangostin-induced cell death and apoptotic responses. Moreover, α-mangostin also repressed tumor growth in accordance with increased levels of p-ASK1, p-p38, cleaved-PARP and cleaved-caspase-3 in the tumor mass from the mouse xenograft model of cervical cancer. In the current study, we provided first evidence to demonstrate that dietary antioxidant α-mangostin could inhibit the tumor growth of cervical cancer cells through enhancing ROS amounts to activate ASK1/p38 signaling pathway and damage the integrity of mitochondria and thereby induction of apoptosis in cervical cancer cells.