title: Silodosin inhibits prostate cancer cell growth via ELK1 inactivation and enhances the cytotoxic activity of gemcitabine.
abstract: BACKGROUND
  Biological significance of ELK1, a transcriptional factor whose phosphorylation is necessary for c-fos proto-oncogene activation, in prostate cancer remains far from fully understood. In this study, we aim to investigate the role of ELK1 in tumor growth as well as the efficacy of a selective α1A-adrenergic blocker, silodosin, in ELK1 activity in prostate cancer cells.
  
  
  METHODS
  We first immunohistochemically determined the levels of phospho-ELK1 (p-ELK1) expression in radical prostatectomy specimens. We then assessed the effects of ELK1 knockdown via short hairpin RNA and silodosin on cell proliferation, migration, and invasion in prostate cancer lines.
  
  
  RESULTS
  The levels of p-ELK1 expression were significantly higher in carcinoma than in benign (P < 0.001) or high-grade prostatic intraepithelial neoplasia (HGPIN) (P = 0.002) as well as in HGPIN than in benign (P < 0.001). Kaplan-Meier and log-rank tests revealed that moderate-strong positivity of p-ELK1 in carcinomas tended to correlate with biochemical recurrence after radical prostatectomy (P = 0.098). In PC3 and DU145 expressing ELK1 (mRNA/protein) but no androgen receptor (AR), ELK1 silencing resulted in considerable decreases in the expression of c-fos as well as in cell migration/invasion and matrix metalloproteinase-2 expression, but not in cell viability. Silodosin treatment reduced the expression/activity of ELK1 in these cells as well as the viability of AR-positive LNCaP and C4-2 cells and the migration of both AR-positive and AR-negative cells, but not the viability of AR-negative or ELK1-negative cells. Interestingly, silodosin significantly increased sensitivity to gemcitabine, but not to cisplatin or docetaxel, even in AR-negative cells.
  
  
  CONCLUSIONS
  ELK1 is likely to be activated in prostate cancer cells and promote tumor progression. Furthermore, silodosin that inactivates ELK1 in prostate cancer cells not only inhibits their growth but also enhances the cytotoxic activity of gemcitabine. Thus, ELK1 inhibition has the potential of being a therapeutic approach for prostate cancer.
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.|Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Takashi
authors: T
authors: Kawahara
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Biology, University of Baghdad College of Science, Baghdad, Iraq.
authors: Ali Kadhim
authors: AK
authors: Aljarah
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Biology, University of Babylon College of Science for Women, Babylon, Iraq.
authors: Hasanain Khaleel
authors: HK
authors: Shareef
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Satoshi
authors: S
authors: Inoue
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Hiroki
authors: H
authors: Ide
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: John D
authors: JD
authors: Patterson
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Eiji
authors: E
authors: Kashiwagi
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Bin
authors: B
authors: Han
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Yi
authors: Y
authors: Li
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Yichun
authors: Y
authors: Zheng
authors: Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors: Hiroshi
authors: H
authors: Miyamoto
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology; D010766:Phosphorylation; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000090063:Proto-Oncogene Mas; D011944:Receptors, Androgen / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000970:Antineoplastic Agents; C494112:ELK1 protein, human; D007211:Indoles; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011944:Receptors, Androgen; D050807:ets-Domain Protein Elk-1; D003841:Deoxycytidine; C095285:silodosin; D000093542:Gemcitabine
keywords: ELK1; drug sensitivity; gemcitabine; immunohistochemistry; silodosin; tumor progression