Abstract
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.
Highlights
DNA damage induced by radiation and chemotherapy drugs promotes cell cycle arrest via activation of cell cycle checkpoints, allowing time for DNA repair to maintain genomic integrity [1, 2]
We demonstrated that hepatocyte growth factor (HGF) moderately activated checkpoint kinase 1 (Chk1) phosphorylation in colon cancer cells by upregulating TopBP1 and RAD51, and promoting TopBP1–ATR complex formation
We demonstrated that AKT is a key mediator of HGF-induced Chk1 phosphorylation, and that TopBP1 and RAD51 were involved in regulating this process
Summary
DNA damage induced by radiation and chemotherapy drugs promotes cell cycle arrest via activation of cell cycle checkpoints, allowing time for DNA repair to maintain genomic integrity [1, 2]. The G1 checkpoint is defective because of p53 mutations; the G2 checkpoint is impaired and necessary for the cell to respond to DNA damage. Recent studies have revealed that Chk phosphorylation has unique clinical implications, including for cancer prognosis and therapeutic sensitivity. There was a strong inverse relationship between phosphorylated Chk (p-Chk1) level and progression-free survival [5]. The relationship between prognosis and p-Chk level in other types of cancer is worthy of further investigation. Inhibition of ATR/Chk has cytotoxic effects and renders cancer cells, especially p53-deficient cancer cells, more sensitive to radiation and to a variety of chemotherapy agents [9–11]. The mechanisms by which Chk phosphorylation is modulated by common pathways involved in tumorigenesis and cancer progression have not been fully elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
