Arsenic trioxide-induced apoptosis in TM4 Sertoli cells: the potential involvement of p21 expression and p53...

Arsenic is a toxic metalloid that exists ubiquitously in the environment, and exhibits carcinogenicity. Conversely, arsenic trioxide (AsTO) has successfully been employed in the treatment of acute promyelocytic leukemia (APL). It has been shown that AsTO efficiently induces apoptosis in the malignant cells of APL in vitro. Although the mechanisms underlying AsTO-induced apoptosis in certain types of cancer cells, such as APL cells, have been delineated, the mechanism underlying AsTO-induced cell death in non-cancer cells remains unknown. In the present study, we examined AsTO-provoked cytotoxicity and cell death mechanism(s) in TM4 Sertoli cells. Exposure of these cells to AsTO generates reactive oxygen species and alters mitochondrial apoptosis, inducing cell death via both caspase-dependent and caspase-independent pathways. AsTO-induced apoptosis was concomitant with the downregulation of p53, phosphorylation of p53 at serine residues, and G2/M cell cycle arrest. Particularly, the interaction of p21 with caspase-3 proteins during AsTO treatment suggested an antiapoptotic role of p21 against genotoxic stresses in TM4 Sertoli cells. However, clinically relevant concentrations of AsTO failed to induce cell death in TM4 Sertoli cells, indicating that these cells could be resistant to cancer treatment. The results presented herein may not represent the actual effect of AsTO on Sertoli cells in vivo. Thus, further studies on the exposure effects of AsTO on the morphology and function of Sertoli cells in animal experiments will provide a more precise knowledge of AsTO cytotoxicity on male reproduction.