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Article

CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation

  • Authors:
    • Min Liang
    • Tiangang Zhao
    • Linfeng Ma
    • Yingjie Guo
  • View Affiliations / Copyright

    Affiliations: School of Life Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
  • Pages: 1322-1330
    |
    Published online on: December 20, 2017
       https://doi.org/10.3892/or.2017.6168
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Abstract

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 µM, 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.
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Copy and paste a formatted citation
Spandidos Publications style
Liang M, Zhao T, Ma L and Guo Y: CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation. Oncol Rep 39: 1322-1330, 2018.
APA
Liang, M., Zhao, T., Ma, L., & Guo, Y. (2018). CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation. Oncology Reports, 39, 1322-1330. https://doi.org/10.3892/or.2017.6168
MLA
Liang, M., Zhao, T., Ma, L., Guo, Y."CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation". Oncology Reports 39.3 (2018): 1322-1330.
Chicago
Liang, M., Zhao, T., Ma, L., Guo, Y."CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation". Oncology Reports 39, no. 3 (2018): 1322-1330. https://doi.org/10.3892/or.2017.6168
Copy and paste a formatted citation
x
Spandidos Publications style
Liang M, Zhao T, Ma L and Guo Y: CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation. Oncol Rep 39: 1322-1330, 2018.
APA
Liang, M., Zhao, T., Ma, L., & Guo, Y. (2018). CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation. Oncology Reports, 39, 1322-1330. https://doi.org/10.3892/or.2017.6168
MLA
Liang, M., Zhao, T., Ma, L., Guo, Y."CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation". Oncology Reports 39.3 (2018): 1322-1330.
Chicago
Liang, M., Zhao, T., Ma, L., Guo, Y."CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation". Oncology Reports 39, no. 3 (2018): 1322-1330. https://doi.org/10.3892/or.2017.6168
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