Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

  • Authors:
    • Yi-Sheng Chou
    • Chueh-Chuan Yen
    • Wei-Ming Chen
    • Yung-Chan Lin
    • Yao-Shan Wen
    • Wei-Ting Ke
    • Jir-You Wang
    • Chun-Yu Liu
    • Muh-Hwa Yang
    • Tain-Hsiung Chen
    • Chien-Lin Liu
  • View Affiliations

  • Published online on: January 20, 2016     https://doi.org/10.3892/ijo.2016.3352
  • Pages: 1187-1194
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Abstract

Polo-like kinase 1 (PLK1), a serine/threonine kinase and an oncogene, is crucial in regulating cell cycle progression. PLK1 also has been demonstrated as a potential target of osteosarcoma (OS) by using short hairpin RNA libraries in lentiviral vectors for screening of protein kinase. In preclinical studies, GSK461364, a potent and selective ATP-competitive PLK1 inhibitor, showed antiproliferative activity against multiple tumor cell lines. In the present study, we evaluated the expression level of PLK1 in OS and explored the cytotoxic mechanism of GSK461364 against OS. PLK1 was significantly overexpressed in OS compared with normal osteoblasts and other types of sarcoma. GSK461364 inhibited PLK1 and caused mitotic arrest by inducing G2/M arrest in OS cells. Moreover, GSK461364 exerted a cytotoxic effect by inducing apoptosis in OS, and induced cellular senescence in OS cell lines, as indicated by an increased senescence-associated β-galactosidase activity and enhanced DcR2 and interleukin-1α expression. In addition, we demonstrated a synergistic cytotoxic effect of GSK461364 and paclitaxel, possibly resulting from combined mitotic arrest. In conclusion, the present study revealed that PLK1 was overexpressed in OS and that GSK461364 exerted its cytotoxic effect on OS by inducing mitotic arrest and subsequent apoptosis and induced cellular senescence; therefore, senescence-associated markers can be used as treatment biomarkers, and a combination of GSK461364 and paclitaxel can potentially treat OS.
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March 2016
Volume 48 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Chou, Y., Yen, C., Chen, W., Lin, Y., Wen, Y., Ke, W. ... Liu, C. (2016). Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel. International Journal of Oncology, 48, 1187-1194. https://doi.org/10.3892/ijo.2016.3352
MLA
Chou, Y., Yen, C., Chen, W., Lin, Y., Wen, Y., Ke, W., Wang, J., Liu, C., Yang, M., Chen, T., Liu, C."Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel". International Journal of Oncology 48.3 (2016): 1187-1194.
Chicago
Chou, Y., Yen, C., Chen, W., Lin, Y., Wen, Y., Ke, W., Wang, J., Liu, C., Yang, M., Chen, T., Liu, C."Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel". International Journal of Oncology 48, no. 3 (2016): 1187-1194. https://doi.org/10.3892/ijo.2016.3352