Arsenic trioxide-induced apoptosis in TM4 Sertoli cells: The potential involvement of p21 expression and p53 phosphorylation
Arsenic trioxide-induced apoptosis in TM4 Sertoli cells: The potential involvement of p21 expression and p53 phosphorylation
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DOI：
10.1016/j.tox.2011.04.013
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发表时间：
2011-07-29
期刊：
影响因子：
4.5
通讯作者：
Kim, Jong-Min
中科院分区：
文献类型：
--
作者：
Kim, Yoon-Jae;Chung, Jin-Yong;Kim, Jong-Min
砷是一种广泛存在于环境中的有毒类金属，具有致癌性。相反，三氧化二砷（AsTO）已成功地用于治疗急性早幼粒细胞白血病（APL）。体外实验表明，AsTO能有效诱导APL恶性细胞凋亡。虽然AsTO诱导的某些类型的癌细胞（如APL细胞）凋亡的潜在机制已被描述，但AsTO诱导的非癌细胞死亡的潜在机制仍不清楚。在本研究中，我们研究了AsTO引起的TM 4 Sertoli细胞的细胞毒性和细胞死亡机制。这些细胞暴露于AsTO会产生活性氧并改变线粒体细胞凋亡，从而通过半胱氨酸蛋白酶依赖性和半胱氨酸蛋白酶非依赖性途径诱导细胞死亡。AsTO诱导的细胞凋亡伴随着p53的下调、p53丝氨酸残基的磷酸化和G2/M期细胞周期阻滞。特别地，在AsTO处理期间p21与半胱天冬酶-3蛋白的相互作用表明p21对TM 4支持细胞中的遗传毒性应激的抗凋亡作用。然而，临床相关浓度的AsTO未能诱导TM 4 Sertoli细胞中的细胞死亡，表明这些细胞可能对癌症治疗具有抗性。本文提供的结果可能不代表AsTO对体内支持细胞的实际作用。因此，在动物实验中进一步研究AsTO对睾丸支持细胞的形态和功能的影响，将提供更准确的认识AsTO对男性生殖的细胞毒性。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.