Effect of nonsteroidal anti‐inflammatory drugs (aspirin and naproxen) on inflammation‐associated proteomic profiles in mouse plasma and prostate during TMPRSS2‐ERG (fusion)‐driven prostate carcinogenesis

Abstract

AbstractRecent preclinical studies have shown that the intake of nonsteroidal anti‐inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2‐ERG fusion‐driven prostate tumorigenesis. Herein, as a follow‐up mechanistic study, employing TMPRSS2‐ERG (fusion) positive tumors and plasma from TMPRSS2‐ERG. Ptenflox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor‐specific cytokines, chemokines, and growth factors/growth signaling‐associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2‐ERG fusion‐driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array‐proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling‐associated molecules between PCa afflicted mice (TMPRSS2‐ERG. Ptenflox/flox, age‐matched noncancerous controls, NSAIDs‐supplemented and no‐drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M‐CSF, IL‐33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors‐ growth signaling‐associated molecules (Chemerin, FGF acidic, Flt‐3 ligand, IGFBP‐5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2‐ERG fusion‐driven prostate tumorigenesis are associated with antiproliferative and anti‐inflammatory effects and possible modulation of the immune cell enriched microenvironment.