Abstract
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 MAPK 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.
Highlights
The Mitogen Activated Protein Kinases (MAPKs) are expressed in all cell types and play key role in gene expression, mitosis, differentiation, proliferation, cell survival, and apoptosis[1]
The methylthiazol tetrazolium (MTT) test was used to investigate the effect of cordycepin on cell viability in primary mouse Leydig cells, MA-10 mouse Leydig tumor cells, and TM4 Sertoli tumor cells (Fig. 1a)
Our results indicated that cordycepin reduced the cell viability in MA-10, TM4, and NT2/D1 cells; activated caspases, induced cell cycle arrest, regulated p38 MAPKs signaling, increased reactive oxygen species (ROS) levels, and inactivated PI3K/AKT signaling in MA-10 mouse Leydig tumor cells
Summary
The Mitogen Activated Protein Kinases (MAPKs) are expressed in all cell types and play key role in gene expression, mitosis, differentiation, proliferation, cell survival, and apoptosis[1]. The p38 MAPKs play an important role in the regulation of balance between cell survival and cell death on the development of various cancers[3]. Recent studies have provided new insight on the control of the balance of autophagy and apoptosis through p38 MAPKs signaling in response to chemotherapeutic agents[6]. Leydig cell tumors are the most prevalent hormone-producing tumors of the testis[12] They account for 1 to 3 percent of all testicular tumors and show two peaks in age incidence: between 5–10 years and 30–35 years[13]. It is important to develop new chemotherapeutic agents that effectively inhibit testicular cancer without having off-target effects
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