Exploring a Novel Mechanism of Docetaxel Resistance in Prostate Cancer
Abstract
Docetaxel (DTX), a semi-synthetic analog of paclitaxel, has emerged as the standard of care for chemotherapy of hormone-resistant prostate cancer (PCa). However, most patients treated with DTX ultimately develop resistance to the drug and succumb to the disease. Therefore, understanding the mechanisms underlying DTX resistance is a priority area in PCa research. Increasingly, it is being suggested that cancer cells may use common pathways for disease aggressiveness/metastatic spread and chemotherapeutic resistance. Therefore, we investigated the role of CXCL12/CXCR4 signaling, which is known to promote invasion and metastasis, in DTX-resistance of PCa cells. Our data demonstrated that CXCL12 treatment rescued the PCa cells from DTX-induced cytotoxicity and G2/M mitotic arrest. Furthermore, the cytoprotective effect of CXCL12 was abolished upon pretreatment of PCa cells with AMD3100 (a small molecule antagonist of CXCR4) or siRNA-mediated silencing of CXCR4, thus confirming the role of CXCR4 in DTX-resistance. Immunofluorescence analyses revealed enhanced polymerization of microtubules in DTX-treated PCa cells. In accordance with this, immunoblot analyses demonstrated increased levels of detyrosinated (glu-) and acetylated (ace-) tubulins, specific markers of the polymerized tubulin, in PCa cells treated with DTX. Cotreatment of CXCL12 abrogated DTX-induced stabilization of microtubules in the PCa cells, an effect that was diminished when the cells were pre-treated with AMD3100. Data from our mechanistic studies suggest the role of PAK4-dependent LIMK1 activation in the CXCL12- induced resistance to docetaxel toxicity and microtubule destabilization. Altogether, our findings demonstrate the role of CXCL12/CXCR4 signaling axis in DTX-resistance of PCa cells and thus could be an attractive target for therapeutic enhancement of DTX.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2014
- Accession Number
- ADA601299
Entities
People
- Ajay Singh
Organizations
- University of South Alabama