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Phosphorylated Akt up‐regulates angiotensin II type‐1 receptor expression in castration resistant prostate cancer
Author(s) -
Kosaka Takeo,
Miyajima Akira,
Shirotake Suguru,
Kikuchi Eiji,
Oya Mototsugu
Publication year - 2011
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21367
Subject(s) - prostate cancer , protein kinase b , medicine , prostate , endocrinology , angiotensin ii , receptor , cancer research , prostate disease , castration , cancer , phosphorylation , biology , hormone , microbiology and biotechnology
BACKGROUND Accumulating evidences has suggested that the renin‐angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration‐resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type‐1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet. METHODS In this study we used C4‐2 and C4‐2AT6 cells, which were PTEN‐null, androgen receptor (AR) positive, PSA‐producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor. RESULTS Western blot analysis revealed C4‐2AT6 cells showed significantly higher pAkt expression than C4‐2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4‐2AT6 tumors obtained from castrated male nude mice. These results indicated that C4‐2AT6 cells acquired elevated pAkt status under androgen‐ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4‐2AT6 more effectively than that of C4‐2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up‐regulated AT1R expression in C4‐2AT6 cells was reduced by LY294002 in a dose‐dependent manner. On the other hand, in C4‐2 cells, serum starvation induced pAkt up‐regulation, which led to an increase of AT1R expression. CONCLUSIONS These findings indicated that up‐regulation of pAkt contributed to elevated AT1R expression in CRPC. Prostate 71:1510–1517, 2011. © 2011 Wiley‐Liss, Inc.