Abstract
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.
Highlights
Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide
We further showed in IGR-CaP1 cells by co-immunoprecipitation that CDC25C interacts with LZTS1, as previously shown by Vecchione www.impactjournals.com/oncotarget et al [18] in 293 cells (Fig. 4C)
The cytotoxicity of taxanebased chemotherapy such as Docetaxel has previously been shown to occur in part through perturbation of the cell cycle and mitotic checkpoints [4] by disrupting microtubules depolymerization leading to cell death
Summary
Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide. It is the most frequent cancer in the United-States and Western countries and is a major cause of cancer death and morbidity. In the past few years, clinical studies have highlighted the value of chemotherapy in metastatic PCa. Docetaxelbased chemotherapy benefit in castration-resistant prostate cancer (CRPC) was demonstrated in 2004 with an increase of overall survival [1,2] and it is until now the standard in first-line chemotherapy in CRPC. A member of the taxane family, inhibits microtubules dynamics which triggers a G2/M cell cycle arrest of tumor cells, and induces apoptosis [3]. Despite the survival benefit provided by this molecule, about half of patients develop drug resistance
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