The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
J Cell Physiol. 2019 Jul;234(7):11871-11881. doi: 10.1002/jcp.27824. Epub 2018 Nov 27.
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.
获得性细胞毒性抗肿瘤药物耐药性是肿瘤治疗中的一个主要临床挑战；然而，其涉及的机制仍知之甚少。在本研究中，我们表明 CtIP（CtBP 的核心抑制剂）的敲低促进了依托泊苷（Eto）处理的 HCT116 细胞的增殖，并缓解了 G2/M 期阻滞。尽管 p53 的重要靶标 p21 和生长阻滞与 DNA 损伤诱导的α（GADD45a）在 CtIP 缺陷型 HCT116 细胞中的表达下调，但 p53 缺失并不影响 Eto 处理后 G2/M 期阻滞。此外，在 Eto 处理后，CtIP 缺陷型 HCT116 细胞中 Chk1 的 Ser317 和 Ser345 以及 CDC25C 的 Ser216 的磷酸化水平低于对照细胞。我们的结果表明，CtIP 可能通过促进 G2/M 期阻滞来增强细胞对 Eto 的敏感性，主要通过 ATR-Chk1-CDC25C 途径而不是 p53-p21/GADD45a 途径。CtIP 的表达可能是预测结直肠癌细胞药物敏感性的有用生物标志物。
