CtIP promotes G2/M arrest in etoposide‐treated HCT116 cells in a p53‐independent manner

• Published in: Journal of cellular physiology Vol. 234; no. 7; pp. 11871 - 11881
• Main Authors: Chen, Hongyu, Shan, Jin, Chen, Dandan, Wang, Ruoxi, Qi, Wenjing, Wang, Hailong, Ke, Yueshuang, Liu, Wenguang, Zeng, Xianlu
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2019
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic drugs; Apoptosis - drug effects; Biomarkers; Cell Cycle Proteins - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell proliferation; CHK1 protein; Clonal deletion; Colorectal cancer; Colorectal carcinoma; CtIP; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; drug sensitivity; Endodeoxyribonucleases - metabolism; Etoposide; Etoposide - pharmacology; G2 Phase Cell Cycle Checkpoints - drug effects; G2/M phase arrest; Gadd45A protein; Gene expression; HCT116 Cells; Humans; M Phase Cell Cycle Checkpoints - drug effects; p53; p53 Protein; Phosphorylation; Sensitivity enhancement; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - drug effects; Tumor Suppressor Protein p53 - genetics; CtIP; drug sensitivity; G2/M phase arrest; etoposide; colorectal cancer; p53
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27824

Acquired resistance to cytotoxic antineoplastic agents is a major clinical challenge in tumor therapy; however, the mechanisms involved are still poorly understood. In this study, we show that knockdown of CtIP, a corepressor of CtBP, promotes cell proliferation and alleviates G2/M phase arrest in etoposide (Eto)‐treated HCT116 cells. Although the expression of p21 and growth arrest and DNA damage inducible α (GADD45a), which are important targets of p53, was downregulated in CtIP‐deficient HCT116 cells, p53 deletion did not affect G2/M arrest after Eto treatment. In addition, the phosphorylation levels of Ser317 and Ser345 in Chk1 and of Ser216 in CDC25C were lower in CtIP‐deficient HCT116 cells than in control cells after Eto treatment. Our results indicate that CtIP may enhance cell sensitivity to Eto by promoting G2/M phase arrest, mainly through the ATR‐Chk1‐CDC25C pathway rather than the p53‐p21/GADD45a pathway. The expression of CtIP may be a useful biomarker for predicting the drug sensitivity of colorectal cancer cells. CtIP can modulate the etoposide sensitivity of HCT116 cells by promoting G2/M phase arrest, which mainly through the ATR‐Chk1‐CDC25C pathway rather than the p53‐p21/GADD45a pathway.