Proton pump inhibitors promote the growth of androgen-sensitive prostate cancer cells through ErbB2, ERK1/2, PI3K/Akt, GSK-3β signaling and inhibition of cellular prostatic acid phosphatase

Abstract Prostate cancer (PCa) is one of the most common cancer in men. Although hormone-sensitive PCa responds to androgen-deprivation, there are no effective therapies for castration-resistant PCa. It has been recently suggested that proton pump inhibitors (PPIs) may increase the risk of certain cancers; however, association with PCa remains elusive. Here, we evaluated the tumorigenic activities of PPIs in vitro , in PCa cell lines and epithelial cells from benign prostatic hyperplasia (BPH) and in vivo , in PCa mice xenografts. PPIs increased survival and proliferation, and inhibited apoptosis in LNCaP cells. These effects were attenuated or absent in androgen-insensitive DU-145 and PC3 cells, respectively. Specifically, omeprazole (OME) promoted cell cycle progression, increased c-Myc expression, ErbB2 activity and PSA secretion. Furthermore, OME induced the phosphorylation of MAPK-ERK1/2, PI3K/Akt and GSK-3β, and blunted the expression and activity of cellular prostatic acid phosphatase. OME also increased survival, proliferation and PSA levels in BPH cells. In vivo , OME promoted tumor growth in mice bearing LNCaP xenografts. Our results indicate that PPIs display tumorigenic activities in PCa cells, suggesting that their long-term administration in patients should be carefully monitored.