title: Simvastatin Up-Regulates Annexin A10 That Can Inhibit the Proliferation, Migration, and Invasion in Androgen-Independent Human Prostate Cancer Cells.
abstract: Statins have recently been studied for their proapoptotic and antimetastatic effects. However, the exact mechanisms of their anticancer actions remain unclear. Using microarrays, we discovered up-regulation of annexin A10 (ANXA10) in PC-3 cells after simvastatin treatment. ANXA10 reportedly has antitumor effects. In this study, we evaluated the effects of simvastatin on ANXA10 signaling in androgen-independent prostate cancer cells.
  
  
  
  PC-3, LNCaP-LA (which were derived from LNCaP cells and cultured in 10% charcoal-stripped fetal bovine serum for 3 months), and DU145 human prostate cancer cell lines were used. Prostate tissues were collected from 60 patients (benign prostatic hyperplasia [BPH], n = 20; prostate cancer with a Gleason score of 7, n = 20; prostate cancer with a Gleason score of 8-10, n = 20) at the time of prostate biopsies performed. We used a nude mouse tumor xenograft model with administration of simvastatin or phosphate-buffered saline via intraperitoneal injection.
  
  
  
  Simvastatin inhibited the proliferation, migration, and invasion of PC-3, LNCaP-LA, and DU145 cells. The expression level of ANXA10 was up-regulated by simvastatin in PC-3, LNCaP-LA, and DU145 cells. Transfection with ANXA10 inhibited PC-3 and LNCaP-LA cells proliferation, migration, and invasion. Knockdown of ANXA10 by siRNA increased the proliferation of PC-3 and LNCaP-LA cells. In a nude mouse xenograft model of PC-3 cells, simvastatin induced both reduction in the tumor size and up-regulation of ANXA10 expression. In human prostate biopsy samples, ANXA10 mRNA expression was significantly lower in the prostate cancer group than in the BPH group. Next, we found that up-regulation of ANXA10 in PC-3 resulted in down-regulation of S100 calcium binding protein A4 (S100A4), which is reportedly correlated with aggressiveness and a worse prognosis for patients with different types of carcinomas. Expression of S100A4 was down-regulated by simvastatin. In PC-3 cells, knockdown of S100A4 by siRNA inhibited the proliferation, migration, and invasion of PC-3 cells.
  
  
  
  Our results suggest that statins inhibit the proliferation, migration, and invasion of androgen-independent prostate cancer cells by up-regulation of ANXA10. Additionally, it is possible that S100A4 plays a role in these effects. Statins may be beneficial in the prevention and/or treatment of prostate cancer. Prostate 77: 337-349, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Miyazawa
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Furuya
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Koike
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D017302:Annexins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: C121387:ANXA10 protein, human; D017302:Annexins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: S100 calcium binding protein A4; annexin A10; prostate cancer; statin