title: Arsenic trioxide-induced apoptosis in TM4 Sertoli cells: the potential involvement of p21 expression and p53 phosphorylation.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Republic of Korea.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Seung Gee
authors.initials: SG
authors.lastname: Lee
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Won Rok
authors.initials: WR
authors.lastname: Kim
authors.forename: Bo Sun
authors.initials: BS
authors.lastname: Joo
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Han
authors.forename: Ki Soo
authors.initials: KS
authors.lastname: Yoo
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis*; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012708:Sertoli Cells / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; D020169:Caspases; D015689:Oncogene Protein p21(ras); D000077237:Arsenic Trioxide