The cellular and molecular mechanisms of cordycepin induced apoptosis in MA-10 mouse Leydig tumor cells

• Main Authors: Bo-SyongPan, 潘博雄
• Other Authors: Bu-Miin Huang
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/28814557656073338183

博士 === 國立成功大學 === 基礎醫學研究所 === 104 === The incidence of testicular cancer between 1999 and 2008 in Taiwan from 0.85 increased to 1.54 per population of hundred thousand people, and radical orchidectomy combined with chemotherapy is the common protocol to treat testicular and Leydig cell cancers. However, these drugs used for chemotherapy could cause drug toxicity, side effects and serious impacts on the quality of life. Thus, people more focus on developing lower side effect chemotherapy drugs to improve prognosis in recent years. Cordycepin, also called 3’-deoxyadenosine, has been identified as a major bioactive metabolite in Cordyceps sinensis. It possesses a wide range of biological effects, including stimulation on steroidogenesis, anti-inflammatory effect, inhibition of platelet aggregation, and anti-cancer effect. We have found that cordycepin could induce testicular tumor cell apoptosis. The p38 MAPKs play important roles in the regulation of balance between cell survival and cell death on the development of various cancers. However, the roles of p38 MAPKs regulating apoptotic effects on Leydig tumor cells remain unclear. In the present study, we showed that cordycepin (3-deoxyadenosine) selectively induced apoptosis in MA-10 mouse Leydig tumor cells through regulating the p38 MAPKs and PI3K/AKT signaling pathways. Cordycepin reduced viability in MA-10, TM4, and NT2/D1 cells, but not cause cell death of primary mouse Leydig cells on moderate concentration. Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP. Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells. Co-treatment with wortmannin or the autophagy inhibitor 3-methyladenine (3-MA) elevated levels of apoptosis in cordycepin-treated MA-10 cells. Moreover, cordycepin activated p53, p21 and TGFß; and downregulated CDK2. The antitumour activity of cordycepin-treated MA-10 cells was significantly distinct in severe combined immunodeficiency (SCID) mice in vivo. These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.