GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cellsReportar como inadecuado

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Molecular Cancer

, 14:122

First Online: 19 June 2015Received: 27 February 2015Accepted: 29 May 2015DOI: 10.1186-s12943-015-0395-0

Cite this article as: Karanika, S., Karantanos, T., Kurosaka, S. et al. Mol Cancer 2015 14: 122. doi:10.1186-s12943-015-0395-0


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.

KeywordsProstate cancer GLIPR1-ΔTM Docetaxel JNK ERK1-2 c-Myc CXCR4 Combination treatment AbbreviationsJNKc- Jun NH2-terminal kinase

ROSReactive oxygen species

ARAndrogen receptor

mCRPCMetastatic castrate resistant prostate cancer

GLIPR1Gene encoding the human glioma pathogenesis-related protein 1

ERK1-2Extracellular signal-regulated kinase1-2

CXCR4C-X-C chemokine receptor type 4

Styliani Karanika, Theodoros Karantanos and Shinji Kurosaka contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12943-015-0395-0 contains supplementary material, which is available to authorized users.

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Autor: Styliani Karanika - Theodoros Karantanos - Shinji Kurosaka - Jianxiang Wang - Takahiro Hirayama - Guang Yang - Sanghee Park


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