Roles of Chk1 in cell biology and cancer therapy

Abstract

The evolutionally conserved DNA damage response (DDR) and cell cycle checkpoints preserve genome integrity. Central to these genome surveillance pathways is a protein kinase, Chk1. DNA damage induces activation of Chk1, which then transduces the checkpoint signal and facilitates cell cycle arrest and DNA damage repair. Significant progress has been made recently towards our understanding of Chk1 regulation and its implications in cancer etiology and therapy. Specifically, a model that involves both spatiotemporal and conformational changes of proteins has been proposed for Chk1 activation. Further, emerging evidence suggests that Chk1 does not appear to be a tumor suppressor; instead, it promotes tumor growth and may contribute to anticancer therapy resistance. Recent data from our laboratory suggest that activating, but not inhibiting, Chk1 in the absence of chemotherapy might represent an innovative approach to suppress tumor growth. These findings suggest unique regulation of Chk1 in cell biology and cancer etiology, pointing to novel strategies for targeting Chk1 in cancer therapy.

Evaluation of CHK1 activation in vulvar squamous cell carcinoma and its potential as a therapeutic target in vitro

“…For example, targeting CHK1 significantly enhances cell killing effect by chemotherapy or radiation therapy in ovarian, triple negative breast, and brain cancers 9. In vitro targeting of CHK1 by inhibitor or siRNA in vulvar cancer cell lines CAL39 and SW954, both harboring p53 mutations,39 leads to a significant reduction in viability which is in line with observation in other cancer types.…”

“…It is known that activated pCHK1 Ser345 can phosphorylate CDC25C at Ser 216 , which promotes the binding of CDC25C to 14‐3‐3 protein and restraining of this complex in the cytoplasm. Thus, scarcity of pCDC25C Ser216 in the nucleus prevents activation of CDK1/Cyclin B1 leading to G2/M arrest 9, 11. Previously, we have reported that 70% of the VSCC cases in this cohort have high expression of pCDC25C Ser216 in the nucleus 25.…”

“…In response to DNA damage, ATR phosphorylates CHK1 at Ser 345 (pCHK1 Ser345 ) and Ser 317 (pCHK1 Ser317 ), which further promotes autophosphorylation at Ser 296 (pCHK1 Ser296 ) 7, 8. Activation of CHK1 leads to phosphorylation of CDC25C at Ser 216 (pCDC25C Ser216 ) 9. The phosphorylated CDC25C is sequestered in the cytoplasm by 14‐3‐3 proteins, which further prevents dephosphorylation of CDK1/Cyclin B1 complex by CDC25C and its activation leading to G2/M arrest 10, 11.…”

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

“…16 Chk1 is an essential kinase in governing cell cycle G 1 /S, S, and G 2 /M phase checkpoints and determining cellular responses to DNA damage. [22][23][24][25][26] In contrast to the well-known utility of Chk1 inhibitors in sensitizing tumors to chemotherapy agents, 23,27,28 Chk1 overexpression or downexpression also occurs in some types of tumors, including breast cancer, ovarian cancer, cervical cancer, and neuroblastoma. 22,[29][30][31][32][33] In our study, we found Chk1 mRNA and protein levels were upregulated in colorectal cancer tissues compared with paired normal tissues, and positively correlated with CCNB1 expression.…”

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

“…26 We analyzed the ATR-dependent Chk1 phosphorylation at Ser-317. Although both cell types, shCtrl and shErk5, showed an increase of Chk1 phosphorylation after incubation with thymidine, the increase was stronger in the latter (Fig.…”