Glyceryl trinitrate-induced cytotoxicity of docetaxel-resistant prostatic cancer cells is associated with differential regulation of clusterin

Metastatic castration resistant prostate cancer (mCRPC) relapse due to acquired resistance to chemotherapy, such as docetaxel, remains a major threat to patient survival. Resistance of mCRPC to docetaxel can be associated with elevated levels of soluble clusterin (sCLU) and growth differentiation factor-15 (GDF-15). Any strategies aiming to modulate sCLU and/or GDF-15 in docetaxel-resistant prostate cancer cells present a therapeutic interest. The present study reports the cytotoxic effect of a nitric oxide donor, glyceryl trinitrate (GTN), on docetaxel-resistant mCRPC human cell lines and demonstrates that GTN displays greater inhibition of cell viability toward docetaxel-resistant mCRPC cells than on mCRPC cells. It is also demonstrated that GTN modulates the level of expression of clusterin (CLU) which is dependent of GDF-15, two markers associated with docetaxel resistance in prostate cancer. The results indicate that GTN represses the level of expression of the cytoprotective isoform of CLU (sCLU) and can increase the level of expression of the cytotoxic isoform (nuclear CLU) in docetaxel resistant cells. Furthermore, it was observed that GTN differentially regulates the level of the precursor form of GDF-15 between resistant and parental cells, and that recombinant GDF-15 can modulate the expression of CLU isoforms and counteract GTN-induced cytotoxicity in resistant cells. A link was established between GDF-15 and the expression of CLU isoforms. The present study thus revealed GTN as a potential therapeutic strategy to overcome docetaxel-resistant mCRPC.