Abstract
BackgroundDocetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells.MethodsThe synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model.ResultsWe found that GLIPR1-ΔΤΜ synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔΤΜ to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did.ConclusionsOur data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0395-0) contains supplementary material, which is available to authorized users.
Highlights
Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer
We investigated the effect of the combination of 1nM docetaxel and 10 μg/ml glioma pathogenesisrelated protein 1 (GLIPR1)-ΔTM on Jun NH2-terminal kinase (JNK) and Extracellular signal-regulated kinase1/2 (ERK1/2)-c-Myc-C-X-C chemokine receptor type 4 (CXCR4) signaling at 24 h for VCaP cells and 48 h for PC-3 cells
Under the same conditions and treatments in both cell lines, we performed MTS and DNA fragmentation assay to evaluate the percentage of survived cells and cell apoptosis, respectively. In both cell lines, the combination treatment of docetaxel and GLIPR1-ΔΤΜ resulted in statistically significant decrease in the percentage of survived cells and increase of apoptotic cells (VCaP: p < 0.001 compared to both single agents in MTS assay, p = 0.02 compared to GLIPR1-ΔΤΜ and p < 0.001 compared to docetaxel according to DNA fragmentation assay, PC-3: p = 0.001 compared to both single agents in MTS assay, p < 0.001 compared to both single agents according to DNA fragmentation assay) but this observation was reversed significantly when we added the JNK inhibitor (SP600125) to the combination docetaxel and GLIPR1-ΔΤΜ (p < 0.001 for both cells lines according to both techniques)
Summary
Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is believed to stabilize microtubules by arresting their de-polymerization, leading to disruption of normal mitosis, G2/M arrest, and inhibition of cell proliferation [6] This agent inhibits Bcl-2 and Bcl-xL activity through decreased gene expression and posttranslational phosphorylation, promoting apoptosis in PCa cells [6,7,8]. Docetaxel increases reactive oxygen species (ROS) production, which promotes JNK activation in androgen receptor (AR)- negative PCa cells [10]. These data suggest that docetaxel promotes cancer cell death through apoptosis mediated by JNK activation
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