Department of Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
J Cell Biochem. 2012 Nov;113(11):3528-35. doi: 10.1002/jcb.24230.
Arsenic trioxide (As(2)O(3)), an effective agent against acute promyelocytic leukemia, has been reported to inhibit the viability of solid tumors cell lines recently. The detailed molecular mechanism underlying the As(2)O(3)-induced inactivation of the cdc2 and possible functional role of PTEN in the observed G2/M arrest has yet to be elucidated. Here, we assessed the role of PTEN in regulation of As(2)O(3)-mediated G2/M cell cycle arrest in Hepatocellular carcinoma cell lines (HepG2 and SMMC7721). After 24 h following treatment, As(2)O(3) induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle. The sustained G2/M arrest by As(2)O(3) is associated with decreased cdc2 protein and increased phospho-cdc2(Tyr15). As(2)O(3) treatment increased Wee1 levels and decreased phospho-Wee1(642). Moreover, As(2)O(3) substantially decreased the Ser473 and Thr308 phosphorylation of Akt and upregulated PTEN expression. Downregulation of PTEN by siRNA in As(2)O(3) -treated cells increased phospho-Wee1(Ser642) while decreased phospho-cdc2(Tyr15), resulting in decreased the G2/M cell cycle arrest. Therefore, induction of G2/M cell cycle arrest by As(2)O(3) involved upregulation of PTEN.
三氧化二砷（As(2)O(3)）是一种有效的急性早幼粒细胞白血病治疗药物，最近有报道称其能够抑制实体肿瘤细胞系的活力。As(2)O(3)诱导 cdc2 失活的详细分子机制以及 PTEN 在观察到的 G2/M 期阻滞中的可能功能作用尚未阐明。在这里，我们评估了 PTEN 在调节肝癌细胞系（HepG2 和 SMMC7721）中 As(2)O(3)介导的 G2/M 细胞周期阻滞中的作用。As(2)O(3)处理 24 小时后，细胞在细胞周期的 G2/M 期呈浓度依赖性积累。As(2)O(3)持续的 G2/M 期阻滞与 cdc2 蛋白减少和磷酸化 cdc2(Tyr15)增加有关。As(2)O(3)处理增加了 Wee1 水平并降低了磷酸化 Wee1(642)。此外，As(2)O(3)还显著降低了 Akt 的 Ser473 和 Thr308 磷酸化并上调了 PTEN 表达。As(2)O(3)处理的细胞中 PTEN 的 siRNA 下调增加了磷酸化 Wee1(Ser642)，同时降低了磷酸化 cdc2(Tyr15)，从而减少了 G2/M 细胞周期阻滞。因此，As(2)O(3)诱导的 G2/M 细胞周期阻滞涉及 PTEN 的上调。
