title: GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells.
abstract: BACKGROUND
  Docetaxel 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. stelakara@hotmail.com.
authors.forename: Styliani
authors.initials: S
authors.lastname: Karanika
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. theodoroskarantanosmd@gmail.com.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Karantanos
authors.affiliation: Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. kurosaka969696@yahoo.co.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kurosaka
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. JWang@mdanderson.org.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. thirayam@med.kitasato-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. GYang@mdanderson.org.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. Spark@mdanderson.org.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Thoracic & Cardio Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. agoltsov@mdanderson.org.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Golstov
authors.affiliation: Department of Urology, Thomas Jefferson University Hospital, Philadelphia, PA, USA. ryuta.tanimoto@jeffersonhospital.org.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tanimoto
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. LLi@mdanderson.org.
authors.forename: Likun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. timthomp@mdanderson.org.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D017384:Sequence Deletion; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: C094538:GLIPR1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D019718:Receptors, CXCR4; D043823:Taxoids; D000077143:Docetaxel