Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer

Am J Pathol. 2012 Mar;180(3):1008-1016. doi: 10.1016/j.ajpath.2011.11.027. Epub 2012 Jan 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Benzimidazoles / pharmacology
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Chemokine CCL2 / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System / physiology
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Grading
  • Neoplasm Recurrence, Local
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / mortality
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptor, Angiotensin, Type 1 / physiology*
  • Tetrazoles / pharmacology
  • Transplantation, Heterologous


  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Biphenyl Compounds
  • Chemokine CCL2
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Phosphatidylinositol 3-Kinases
  • candesartan cilexetil