Influence of chk1 and plk1 silencing on radiation- or cisplatin-induced cytotoxicity in human malignant cells |
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Authors: | Qinglei Gao Xiaoyuan Huang Duozhuang Tang Yang Cao Gang Chen Yunping Lu Liang Zhuang Shixuan Wang Gang Xu Jianfeng Zhou Ding Ma |
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Institution: | (1) Cancer Biology Research Center, TongJi Hospital, TongJi Medical College, Huazhong University of Science & Technology, 1095 Jie-Fang Avenue, WuHan, HuBei, 430030, P. R. China |
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Abstract: | The G2/M checkpoint is an attractive pathway for targeting and sensitizing tumor cells to cancer treatment. Abrogation of
the G2/M checkpoint by targeting molecules, such as checkpoint kinase 1 (chk1), increases DNA breakage and sensitizes tumor
cells to anti-tumoral agents. However, most of the previously described G2/M abrogators are actually targeting the G2-M border
checkpoints rather than mitotic checkpoints. This prompted us to test the effects of combined targeting of chk1 and a critical
regulator of mitosis, polo-like kinase 1 (plk1). Chk1 and plk1 were found to be co-expressed in 70% of primary neoplastic
tissues we examined. Asynchronized tumor cells were treated with different DNA damaging-agents to activate G1/S, S or G2/M
checkpoints. Either chk1 or plk1-specific antisense oligodeoxynucleotides (ASODN) enhanced DNA damaging agent-induced apoptosis.
When used in combination, however, chk1- plus plk1-specific ASODN failed to produce synergistic effects. Moreover, selective
targeting of plk1 or chk1 in tumor xenografts of mice by oncolytic adenovirus mutants demonstrated potent anti-tumoral efficacy
in the presence of low dose cisplatin. Again, combined targeting of chk1 and plk1 did not further enhance anti-tumoral efficacy.
We concluded that combined targeting of chk1 and plk1 was not superior to either targeting chk1 or plk1 alone, which suggested
that chk1 and plk1 silencing might overlap in their mechanism of action. Whether combined targeting of chk1 with other, more
specific mitotic regulators would synergistically sensitize tumor to anti-neoplastic therapeutics needs to be further clarified.
Qinglei Gao and Xiaoyuan Huang contributed equally to this work. |
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Keywords: | Checkpoint kinase 1 Polo-like kinase 1 Cell cycle Apoptosis |
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