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

Molecular Cancer

Research

Jianxiang Wang¹  Sanghee Park¹  Theodoros Karantanos¹  Guang Yang¹  Likun Li¹  Styliani Karanika¹  Timothy C. Thompson¹  Alexei A. Golstov²  Shinji Kurosaka³  Takahiro Hirayama³  Ryuta Tanimoto⁴ 

[1] Department of Genitourinary Medical Oncology – Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA;Department of Thoracic & Cardio Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan;Department of Urology, Thomas Jefferson University Hospital, Philadelphia, PA, USA;

关键词: Prostate cancer;    GLIPR1-ΔTM;    Docetaxel;    JNK;    ERK1/2;    c-Myc;    CXCR4;    Combination treatment;   

DOI  :  10.1186/s12943-015-0395-0

 received in 2015-02-27, accepted in 2015-05-29,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Karanika et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.