Ets-1 and hypoxia inducible factor-1alpha inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer.
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.
Kosaka
Takeo
T
Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Miyajima
Akira
A
Shirotake
Suguru
S
Kikuchi
Eiji
E
Hasegawa
Masanori
M
Mikami
Shuji
S
Oya
Mototsugu
M
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
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