CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation
CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation
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DOI：
10.3892/or.2017.6168
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发表时间：
2018-03-01
期刊：
影响因子：
4.2
通讯作者：
Guo, Yingjie
中科院分区：
文献类型：
--
作者：
Liang, Min;Zhao, Tiangang;Guo, Yingjie
抑制检查点激酶1 （CHK1）是一种很有前途的治疗策略，可以提高dna损伤药物在胰腺癌中的有效性。然而，由于CHK1在DNA损伤反应（DDR）通路中的多重作用，CHK1抑制剂化学致敏的分子机制尚不明确。在本研究中，我们探索了特异性CHK1抑制剂LY2603618单独或联合吉西他滨对5种胰腺癌细胞系的抗肿瘤机制。LY2603618对胰腺癌细胞系的抑制作用，IC50值在0.89 ~ 2.75 μ M之间，但细胞死亡有限。重要的是，LY2603618治疗胰腺癌细胞系降低了pCDC25C、pCDK1和pCDK2的水平，并伴有DNA损伤和RRM1/2下调。此外，LY2603618与吉西他滨协同治疗可诱导胰腺癌细胞生长抑制和凋亡。机制研究表明，CHK1抑制吉西他滨致敏与cdk依赖性RRM1/2下调和DNA损伤增强有关。这些发现为进一步开发CHK1抑制剂联合吉西他滨治疗胰腺癌提供了基础。
Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0.89 to 2.75 mu M, but limited cell death. Importantly, treatment of pancreatic cancer cell lines with LY2603618 reduced the levels of pCDC25C, pCDK1, and pCDK2, accompanied by DNA damage and RRM1/2 downregulation. Furthermore, LY2603618 synergized with gemcitabine treatment to induce growth inhibition and apoptosis in pancreatic cancer cells. Mechanistic investigations showed that gemcitabine sensitization by CHK1 inhibition was associated with CDK-dependent RRM1/2 downregulation and DNA damage enhancement. These findings provide a basis for further development of combining CHK1 inhibitors and gemcitabine to treat pancreatic cancer.