Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer.
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is reported to contribute to tumor progression and is regulated by the renin-angiotensin system in hypertensive disease. In this study, we investigated the clinical outcome of MCP-1 expression in patients with prostate cancer (CaP) and the regulation of MCP-1 through angiotensin II (AngII) type 1 receptor (AT1R) in CaP. Specimens were obtained from 138 CaP patients and analyzed by immunostaining for both MCP-1 and macrophages. We investigated the regulation of MCP-1 expression through AT1R both in vivo and in vitro using three human prostate cancer cell lines: LNCaP, C4-2, and C4-2AT6. Specimens with a high Gleason score (≥7) and a high pathological classification (≤pT3), and those with castration-resistant prostate cancer showed significantly higher MCP-1 expression and higher macrophage infiltration than low malignant potential CaP. High MCP-1 expression in CaP correlated significantly with high prostate-specific antigen (PSA) recurrence rates. AngII induced significantly higher MCP-1 levels in C4-2AT6 than in LNCaP, whereas AT1R blockade (ARB) inhibited MCP-1 production via the inhibition of the PI3K/Akt pathway in C4-2AT6. ARB also significantly suppressed MCP-1 expression in C4-2AT6 tumors. Our study is the first to demonstrate that both high MCP-1 expression and high macrophage infiltration in CaP specimens correlate with a high PSA recurrence rate and that ARB inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer.
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Suguru
S
Shirotake
Department of Urology, Keio University School of Medicine, Tokyo, Japan. Electronic address: akiram@sc.itc.keio.ac.jp.
Akira
A
Miyajima
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Takeo
T
Kosaka
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Nobuyuki
N
Tanaka
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Eiji
E
Kikuchi
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Shuji
S
Mikami
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Yasunori
Y
Okada
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Mototsugu
M
Oya
D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014183:Transplantation, Heterologous
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D019869:Phosphatidylinositol 3-Kinases; C077793:candesartan cilexetil