Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2013 Dec 20;8(12):e83312. doi: 10.1371/journal.pone.0083312. eCollection 2013.
A number of studies have shown that apoptosis resistance can be observed in multiple human tumors; however the detailed mechanism remains unclear. In the present study, we demonstrated that the abnormal overexpression of the C terminus of Hsc70-interacting protein (CHIP) induced apoptosis resistance by regulating the AKT/FoxO/Bim signaling pathway in the breast cancer cell MCF7 and the human non-tumorigenic cell MCF10A. We found that CHIP overexpression in MCF7 and MCF10A cells activated AKT and inhibited the Forkhead box O (FoxO) transcription factors FoxO1, FoxO3, and FoxO4, thereby inhibiting transcription of the target genes bim and pten. Inhibition of PI3K by a chemical reagent revealed that these events may be critical for CHIP-induced apoptosis resistance. We also determined that inhibition of FoxO3 by CHIP led to the decrease in PTEN and further activated the AKT survival pathway. We corroborated our findings in breast cancer tissues. In general, the CHIP-modulated AKT/FoxO/Bim signaling pathway was shown to induce apoptosis resistance by decreasing the protein level of the tumor suppressor PTEN in both transcriptional and post-translational regulations.
许多研究表明，细胞凋亡抵抗可在多种人类肿瘤中观察到；然而，其详细机制尚不清楚。在本研究中，我们证明异常过表达热休克蛋白 70 相互作用蛋白（CHIP）的 C 末端通过调节乳腺癌细胞 MCF7 和人非肿瘤细胞 MCF10A 中的 AKT/FoxO/Bim 信号通路诱导细胞凋亡抵抗。我们发现 CHIP 在 MCF7 和 MCF10A 细胞中的过表达激活了 AKT 并抑制了叉头框 O（FoxO）转录因子 FoxO1、FoxO3 和 FoxO4，从而抑制了靶基因 bim 和 pten 的转录。通过化学试剂抑制 PI3K 表明，这些事件可能对 CHIP 诱导的细胞凋亡抵抗至关重要。我们还确定 CHIP 抑制 FoxO3 导致 PTEN 减少，并进一步激活 AKT 存活途径。我们在乳腺癌组织中证实了这些发现。一般来说，CHIP 调节的 AKT/FoxO/Bim 信号通路通过在转录和翻译后水平降低肿瘤抑制因子 PTEN 的蛋白水平诱导细胞凋亡抵抗。
