Aberrant Polo-like kinase 1-Cdc25A pathway in metastatic hepatocellular carcinoma.
OBJECTIVE
Most studies on pathogenesis of tumor metastasis focus on cell adhesion and migration. Little is understood of how cell cycle pathways critically affect cell fate of metastatic cells and their sensitivity to anticancer drugs. In this study, we investigated cell cycle checkpoint progression and regulation in the presence of cisplatin in metastatic hepatocellular carcinoma (HCC) cells.


METHODS
Cisplatin-mediated cell cycle progression and Polo-like kinase 1 (Plk1)-Cdc25A pathway were compared between metastatic and nonmetastatic HCC cells by flow cytometry, Western blots, and reverse transcription-PCR. Cdc25A expression in clinical HCC samples was detected using immunohistochemistry and its association with clinical HCC metastasis was analyzed.


RESULTS
Cisplatin induced degradation of Cdc25A in nonmetastatic HCC cells but not in metastatic HCC cells. Hence, metastatic HCC cells showed defective S-M cell cycle phase arrest and continued to enter mitosis. Tumor expression of Cdc25A was strongly associated with metastatic diseases in HCC patients, and elevated Cdc25A expression significantly correlated with HCC tumor-node-metastasis staging and venous invasion. Metastatic HCC cells did not show down-regulation of Plk1 that was normally induced by DNA damage. Blockage of Plk1 expression in metastatic HCC cells initiated Cdc25A degradation in response to DNA damage, suggesting that Plk1 could be an upstream regulator of Cdc25A. Deregulated Plk1-Cdc25A pathway in metastatic HCC cells and primary tumors did not result in drug-induced mitotic catastrophe but rather in accumulation of damaged DNA due to checkpoint adaptation.


CONCLUSIONS
Metastatic HCC cells showed a defective S-M checkpoint following cisplatin treatment and potential aberrant checkpoint adaptation, which might result from deregulation of Plk1-Cdc25A pathway.
Wang
Xiao Qi
XQ
Department of Surgery, The University of Hong Kong, Hong Kong, People's Republic of China.
Zhu
Yong Qiang
YQ
Lui
Karen S
KS
Cai
Qi
Q
Lu
Ping
P
Poon
Ronnie T
RT
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D020687:cdc25 Phosphatases / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D002945:Cisplatin; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C517004:CDC25A protein, human