title: miR-130a activates apoptotic signaling through activation of caspase-8 in taxane-resistant prostate cancer cells.
abstract: BACKGROUND
  The acquisition of drug resistance is one of the most malignant phenotypes of cancer and identification of its therapeutic target is a prerequisite for the development of novel therapy. MicroRNAs (miRNAs) have been implicated in various types of cancer and proposed as potential therapeutic targets for patients. In the present study, we aimed to identify miRNA that could serve as a therapeutic target for taxane-resistant prostate cancer.
  
  
  METHODS
  In order to identify miRNAs related to taxane-resistance, miRNA profiling was performed using prostate cancer PC-3 cells and paclitaxel-resistant PC-3 cell lines established from PC-3 cells. Microarray analysis of mRNA expression was also conducted to search for potential target genes of miRNA. Luciferase reporter assay was performed to examine miRNA binding to the 3'-UTR of target genes. The effects of ectopic expression of miRNA on cell growth, tubulin polymerization, drug sensitivity, and apoptotic signaling pathway were investigated in a paclitaxel-resistant PC-3 cell line.
  
  
  RESULTS
  The expression of miR-130a was down-regulated in all paclitaxel-resistant cell lines compared with parental PC-3 cells. Based on mRNA microarray analysis and luciferase reporter assay, we identified SLAIN1 as a direct target gene for miR-130a. Transfection of a miR-130a precursor into a paclitaxel-resistant cell line suppressed cell growth and increased the sensitivity to paclitaxel. Lastly, ectopic expression of miR-130a did not affect the polymerized tubulin level, but activated apoptotic signaling through activation of caspase-8.
  
  
  CONCLUSIONS
  Our results suggested that reduced expression of miR-130a may be involved in the paclitaxel-resistance and that miR-130a could be a therapeutic target for taxane-resistant prostate cancer patients.
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Health Care Center, Toyohashi University of Technology, Toyohashi, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Japan.
authors.forename: Kyojiro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Deguchi
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; D043823:Taxoids; C080625:taxane; D053181:Caspase 8
keywords: caspase-8; miR-130a; microRNA; prostate cancer; taxane-resistance