Zhu Jianjun, Yan Fang, Tao Jia, Zhu Xiaohua, Liu Jiayou, Deng Shishan, Zhang Xiaoming
Department of Human Anatomy and Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong, China.
School of Life Sciences, Chongqing University, Chongqing, China.
Cancer Sci. 2018 Mar;109(3):656-665. doi: 10.1111/cas.13495. Epub 2018 Feb 16.
Cell division cycle 37 (Cdc37) is an important partner for heat shock protein 90 (HSP90), assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulates cell survival in colorectal carcinoma (CRC) remain unclear. Here, we investigated the expression of Cdc37 and its clinical significance in CRC, and systematically explored the role and the underlying mechanism of Cdc37 in CRC cell survival both in vitro and in vivo. Our results showed that Cdc37 was remarkably up-regulated in CRC, which facilitated cell survival mainly by promoting cell proliferation, G1-S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of cyclin-dependent kinase 4 (CDK4) to activate the retinoblastoma 1 (RB1) signaling pathway, followed by increased expression of Bcl-2 and Bcl-xL, which ultimately promoted cell survival in CRC. Moreover, knockdown of CDK4 reversed the Cdc37-mediated effect in promoting the progression of CRC. Our findings showed that Cdc37 played a critical role in promoting CRC cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patients.
细胞分裂周期37（Cdc37）是热休克蛋白90（HSP90）的重要伴侣，协助分子伴侣活性，特别是在蛋白激酶的调节方面。鉴于其对细胞生长途径的影响，Cdc37已被讨论为致癌作用中的潜在中间体。然而，迄今为止，Cdc37调节结直肠癌（CRC）细胞存活的潜在功能作用和分子机制仍不清楚。在此，我们研究了Cdc37在CRC中的表达及其临床意义，并系统地探讨了Cdc37在体外和体内CRC细胞存活中的作用及潜在机制。我们的结果表明，Cdc37在CRC中显著上调，主要通过促进细胞增殖、G1-S期转换和抑制细胞凋亡来促进细胞存活。我们的数据进一步表明，Cdc37增加细胞周期蛋白依赖性激酶4（CDK4）的稳定性以激活视网膜母细胞瘤1（RB1）信号通路，随后Bcl-2和Bcl-xL表达增加，最终促进CRC中的细胞存活。此外，敲低CDK4可逆转Cdc37介导的促进CRC进展的作用。我们的研究结果表明，Cdc37通过增加CDK4稳定性以激活RB1信号通路在促进CRC细胞存活中起关键作用。因此，Cdc37可能作为CRC患者的潜在治疗靶点。
