Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer
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Nader Al Nakouzi1,2,6, Sophie Cotteret1,2,6, Frédéric Commo2,6, Catherine Gaudin1,2,6, Shanna Rajpar1,2,5,6, Philippe Dessen3,6, Philippe Vielh2,4,6, Karim Fizazi1,2,5,6 and Anne Chauchereau1,2,6
1 Prostate Cancer Group, INSERM U981, Gustave Roussy, Villejuif, F-94805, France;
2 INSERM U981, LabEx LERMIT, Gustave Roussy,
3 INSERM U985, Gustave Roussy;
4 Department of Pathology, HistoCytoPathology Unit, Translational Research Laboratory and Biobank, Gustave Roussy;
5 Department of Medicine, Gustave Roussy;
6 University Paris-Sud 11, France.
Anne Chauchereau, email:
Keywords: Prostate cancer, chemoresistance, LZTS1, CDC25C, PLK1, CHEK1
Received: November 4, 2013 Accepted: January 6, 2014 Published: January 6, 2014
Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance. Understanding resistance mechanisms, which are largely unknown, will allow identification of predictive biomarkers and therapeutic targets. We established resistant IGR-CaP1 prostate cancer cell lines for different doses of Docetaxel. We investigated gene expression profiles by microarray analyses in these cell lines and generated a signature of 99 highly differentially expressed genes potentially implicated in chemoresistance. We focused on the role of the cell cycle regulator LZTS1, which was under-expressed in the Docetaxel-resistant cell lines, its inhibition resulting from the promoter methylation. Knockdown of LZTS1 in parental cells with siRNA showed that LZTS1 plays a role in the acquisition of the resistant phenotype. Furthermore, we observed that targeting CDC25C, a partner of LZTS1, with the NSC663284 inhibitor specifically killed the Docetaxel-resistant cells. To further investigate the role of CDC25C, we used inhibitors of the mitotic kinases that regulate CDC25C. Inhibition of CHEK1 and PLK1 induced growth arrest and cell death in the resistant cells. Our findings identify an important role of LZTS1 through its regulation of CDC25C in Docetaxel resistance in prostate cancer and suggest that CDC25C, or the mitotic kinases CHEK1 and PLK1, could be efficient therapeutic targets to overcome Docetaxel resistance
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