The Role of GADD45a in Docetaxel Sensitivity in Prostate Cancer

Most prostate cancer related deaths occur in patients with metastatic castration resistant prostate cancer (CRPC).  Docetaxel along with prednisone is the currently FDA-approved drug for the treatment of metastatic CRPC. However, after an initial response to docetaxel, about 80% of patients progress within 12 months and median time to progression is 6 months. Presently there are limited treatment options for patients with CRPC who have progressed on or after docetaxel chemotherapy.  Docetaxel acts through apoptotic and cell cycle regulation pathways. Previous results from our lab have shown that Growth Arrest and DNA Damage inducible alpha (GADD45a), a gene involved in the apoptotic pathway and cell cycle control, is down regulated in Du145 prostate cancer cells by methylation of 4 CpG dinucleotides in the 5’ UTR of the gene.  Moreover, upregulation of GADD45a by treatment with the methylation inhibitor, azacitidine, or by recombinant expression resulted in enhanced sensitivity to docetaxel treatment indicating the role of GADD45a in docetaxel mediated cytotoxicity. In this project, we examined the role of GADD45a in azacitidine-mediated sensitivity to docetaxel.  Du145 cells in which GADD45a was stably knocked down (Du145 GADD45─) were treated with azacitidine followed by docetaxel. Cell viability was measured by cell titer blue assay. Du145 wild type and control shRNA transfected cells were used as controls. We observed significant reduction in docetaxel sensitivity in Du145 GADD45─ cells compared to control cells. This indicates that GADD45a is a key gene in docetaxel sensitivity and a potential therapeutic target in prostate cancer.