title: Ets-1 and hypoxia inducible factor-1alpha inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer.
abstract: BACKGROUND
  Accumulating evidences have suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that hormone-refractory prostate cancer (HRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that the AT1R blocker (ARB) exerted protective effects by inhibiting angiogenesis. However, the downstream transcriptional factors induced by Ang II in prostate cancer cells have not been fully elucidated yet.
  
  
  METHODS
  Three human prostate cancer cell lines: LNCap, C4-2 and C4-2AT6 were used and analyzed. C4-2AT6 cells were established by culture in androgen-ablated conditioned medium for 6 months.
  
  
  RESULTS
  C4-2AT6 cells showed significantly higher AT1R expression, accompanied by higher HIF-1alpha and Ets-1 expression in the nucleus. In C4-2AT6 cells, VEGF production was significantly higher than in C4-2 cells and LNCaP cells. These results suggested that HRPC exhibited aggressive angiogenic properties, accompanied by up-regulated HIF-1alpha and Ets-1. Ang II stimulated VEGF production in C4-2 cells and C4-2AT6 cells but not in LNCaP cells. ARB significantly inhibited VEGF production. Western blot analysis demonstrated that AngII induced nuclear expression of HIF-1alpha and Ets-1 in C4-2 and C4-2AT6 cells, but not in LNCaP cells. ARB significantly inhibited HIF-1alpha and Ets-1 induction in C4-2 and C4-2AT6 cells.
  
  
  CONCLUSIONS
  This study suggests that AT1R blockade may have a significant impact on HRPC through the inhibition of HIF-1alpha and Ets-1 and the resulting suppression of angiogenesis. Our results provide the molecular basis of the clinical benefit of ARB as an angiogenic inhibitor in HRPC.
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.forename: Suguru
authors.initials: S
authors.lastname: Shirotake
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050784:Proto-Oncogene Protein c-ets-1; D044140:Receptor, Angiotensin, Type 1