Influence of chk1 and plk1 silencing on radiation- or cisplatin-induced cytotoxicity in human malignant cells.
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.
Gao
Qinglei
Q
Cancer Biology Research Center, TongJi Hospital, TongJi Medical College, Huazhong University of Science & Technology, 1095 Jie-Fang Avenue, WuHan, HuBei 430030, PR China.
Huang
Xiaoyuan
X
Tang
Duozhuang
D
Cao
Yang
Y
Chen
Gang
G
Lu
Yunping
Y
Zhuang
Liang
L
Wang
Shixuan
S
Xu
Gang
G
Zhou
Jianfeng
J
Ma
Ding
D
D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference / Q000502:physiology*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D002945:Cisplatin; D020319:Oligodeoxyribonucleotides, Antisense; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse