GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells

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.

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

“…Constitutively activated ERK1/2 was maintained by CXCR4, which was also upregulated in resistant cells. It is now commonly accepted that constitutive activation of the CXCR4, ERK1/2, and c-Myc signaling loop plays a major role in prostate tumorigenesis [ 15 , 16 ].…”

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

“…A DNA fragmentation analysis was performed using a Cell Death Detection ELISA (Roche Applied Science, Indianapolis, IN) as previously described [32]. …”

Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth

“…androgen deprivation therapy or the application of androgen receptor antagonists, are initially effective in treating prostate cancer (PC), but the disease generally recurs with metastasis due to non-responsiveness to these treatments. [1][2][3] These therapies lower the level of the androgens testosterone and dihydrotestosterone or interfere with the binding of androgen ligands to androgen receptors (AR), respectively, 4 but the disease typically progresses despite application of these treatments, with the AR typically being expressed in truncated or mutated form. 5 Although the mechanism for cancer progression after androgen deprivation/AR antagonist treatment is not fully understood, possible explanations include: i) AR gene amplification, ii) constitutive activation of AR, iii) AR mutation or truncation, iv) activation of AR by growth factors, and/or v) activation of AR by alternative androgen independent signaling pathways.…”