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The role of SKP2 in docetaxel response and resistance in prostate cancer.

e15058 Background: Docetaxel, a microtubule-targeting agent, is the current standard of care for symptomatic metastatic castrate-resistant prostate cancer. Understanding the mechanisms underlying docetaxel resistance may help clinicians tailor patient treatment and develop strategies to overcome resistance. Our analysis identified the underexpression of S-phase kinase associated protein 2 (SKP2) as a potential novel docetaxel resistance marker. SKP2 ubiquitinates and degrades p27Kip1, a tumor suppressor which inhibits kinases that control progression to the S-phase of the cell cycle. Elevated SKP2 degrades p27Kip1, which in turn leads to uncontrolled proliferation. In this study, we investigated the effect of modulating SKP2 expression on docetaxel-response in a human prostate cancer cell line, DU145.


METHODS
Publicly available datasets were analyzed to identify transcripts whose expression correlated with docetaxel-resistance. The impact on docetaxel-response from changing the expression levels of one of the candidate biomarkers, SKP2, was evaluated using an siRNA approach. Loss of expression was confirmed with quantitative RTPCR and Western blot. Cytotoxicity was measured using a modified MTT assay.


RESULTS
SKP2 was found to be underexpressed in taxane-resistant lines with a median p-value of 7.31E-4. Loss of SKP2 expression decreased proliferation in DU145 cells. However, SKP2 knockdown did not have a statistically significant effect on docetaxel-sensitivity.


CONCLUSIONS
Our analysis identified SKP2 as a potential novel docetaxel resistance marker. Knockdown experiments confirmed its role in proliferation but did not have a statistically significant effect on docetaxel-sensitivity. The clinical and biologic significance of SKP2 in determining docetaxel-sensitivity is yet to be determined.