Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
Mol Cell Biochem. 2017 Dec;436(1-2):29-38. doi: 10.1007/s11010-017-3075-0. Epub 2017 Jun 1.
The ATR/checkpoint kinase 1 (Chk1) pathway plays an essential role in modulating the DNA damage response and homologous recombination. Particularly, Chk1 phosphorylation is related to cancer prognosis and therapeutic resistance. Some receptor tyrosine kinases participate in the regulation of Chk1 phosphorylation; however, the effect of hepatocyte growth factor (HGF) on Chk1 phosphorylation is unknown. In the present study, we demonstrated that HGF moderately activated Chk1 phosphorylation in colon cancer cells by upregulating TopBP1 and RAD51, and promoting TopBP1-ATR complex formation. Furthermore, AKT activity, which was promoted by HGF, served as an important mediator linking HGF/MET signaling and Chk1 phosphorylation. Depleting AKT activity attenuated basal expression of p-Chk1 and HGF-induced Chk1 activation. Moreover, AKT activity directly regulated TopBP1 and RAD51 expression. AKT inhibition suppressed HGF-induced upregulation of TopBP1 and RAD51, and enhanced TopBP1/ATR complex formation. Our results show that HGF was involved in regulating Chk1 phosphorylation, and further demonstrate that AKT activity was responsible for this HGF-induced Chk1 phosphorylation. These findings might potentially result in management of prognosis and therapeutic sensitivity in cancer therapy.
ATR/检查点激酶 1（Chk1）通路在调节 DNA 损伤反应和同源重组中起着至关重要的作用。特别是，Chk1 的磷酸化与癌症预后和治疗耐药性有关。一些受体酪氨酸激酶参与 Chk1 磷酸化的调节；然而，肝细胞生长因子（HGF）对 Chk1 磷酸化的影响尚不清楚。在本研究中，我们证明 HGF 通过上调 TopBP1 和 RAD51，促进 TopBP1-ATR 复合物形成，适度激活结肠癌细胞中的 Chk1 磷酸化。此外，HGF 促进的 AKT 活性作为连接 HGF/MET 信号和 Chk1 磷酸化的重要介质。耗尽 AKT 活性会减弱基础表达的 p-Chk1 和 HGF 诱导的 Chk1 激活。此外，AKT 活性直接调节 TopBP1 和 RAD51 的表达。AKT 抑制抑制了 HGF 诱导的 TopBP1 和 RAD51 的上调，并增强了 TopBP1/ATR 复合物的形成。我们的研究结果表明 HGF 参与调节 Chk1 磷酸化，并进一步证明 AKT 活性是 HGF 诱导的 Chk1 磷酸化的原因。这些发现可能会对癌症治疗的预后和治疗敏感性的管理产生影响。
