Vitexin suppresses autophagy to induce apoptosis in hepatocellular carcinoma via activation of the JNK signaling pathway

Abstract

// Jin-Dan He 1, * , Zhen Wang 1, * , Shi-Peng Li 1, 4, * , Yan-Jie Xu 1, * , Yao Yu 1 , Yi-Jie Ding 1 , Wen-Li Yu 2 , Rong-Xin Zhang 5 , Hai-Ming Zhang 1, 3 , Hong-Yin Du 2, 1 1 First Central Clinical College, Tianjin Medical University, Tianjin 300192, P.R. China 2 Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, P.R. China 3 Department of Liver Transplantation, Oriental Organ Transplant Center of Tianjin First Central Hospital, Key Laboratory of Organ Transplantation of Tianjin, Tianjin 300192, P.R. China 4 Department of General Surgery, The People’s Hospital of Jiaozuo City, Jiaozuo 454002, P.R. China 5 Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Basic Medical College, Tianjin Medical University, Tianjin 300070, P.R. China * These authors have contributed equally to this work Correspondence to: Hong-Yin Du, email: duhongyin2014@yeah.net Hai-Ming Zhang, email: zhanghaiming@medmail.com.cn Keywords: vitexin, hepatocellular carcinoma, autophagy, apoptosis, JNK signaling Received: June 15, 2016      Accepted: August 15, 2016      Published: August 31, 2016 ABSTRACT Vitexin, a flavonoids compound, is known to exhibit broad anti-oxidative, anti-inflammatory, analgesic, and antitumor activity in many cancer xenograft models and cell lines. The purpose of this study was to investigate the antitumor effects and underlying mechanisms of vitexin on hepatocellular carcinoma. In this study, we found that vitexin suppressed the viability of HCC cell lines (SK-Hep1 and Hepa1-6 cells) significantly. Vitexin showed cytotoxic effects against HCC cell lines in vitro by inducing apoptosis and inhibiting autophagy. Vitexin induced apoptosis in a concentration-dependent manner, and caused up-regulations of Caspase-3, Cleave Caspase-3, and a down-regulation of Bcl-2. The expression of autophagy-related protein LC3 II was significantly decreased after vitexin treatment. Moreover, western blot analysis presented that vitexin markedly up-regulated the levels of p-JNK and down-regulated the levels of p-Erk1/2 in SK-Hep1 cells and Hepa1-6 cells. Cotreatment with JNK inhibitor SP600125, we demonstrated that apoptosis induced by vitexin was suppressed, while the inhibition of autophagy by vitexin was reversed. The results of colony formation assay and mouse model confirmed the growth inhibition role of vitexin on HCC in vitro and in vivo . In conclusion, vitexin inhibits HCC growth by way of apoptosis induction and autophagy suppression, both of which are through JNK MAPK pathway. Therefore, vitexin could be regarded as a potent therapeutic agent for the treatment of HCC.