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. (1st May 2019)

• Record Type: Journal Article
• Authors: Gesmundo, Iacopo; Di Blasio, Laura; Banfi, Dana; Villanova, Tania; Fanciulli, Alessandro; Favaro, Enrica; Gamba, Giacomo; Musuraca, Chiara; Rapa, Ida; Volante, Marco; Munegato, Stefania; Papotti, Mauro; Gontero, Paolo; Primo, Luca; Ghigo, Ezio; Granata, Riccarda
• Is Part Of: Cancer letters. Volume 449(2019)
• Page Start: 252
• Page End: 262
• Publication Date: 2019-05-01
• Subjects: Proton pump inhibitors -- Prostate cancer cells -- Primary prostate epithelial cells -- Prostate specific antigen -- Cellular prostatic acid phosphatase; ADT androgen deprivation therapy -- AR androgen receptor -- Bcl-2 B-cell lymphoma-2 -- BPH benign prostatic hyperplasia -- BME basement extract -- BrdU 5-bromo-2-deoxyuridine -- BSA bovine serum albumin -- CGA chromogranin A -- cPAcP cellular prostatic acid phosphatase -- CRPC castration-resistant prostate cancer -- DMEM Dulbecco's Modified Eagle's medium -- DTX docetaxel -- EDTA ethylenediaminetetraacetic acid -- ELISA enzyme-linked immunosorbent assay -- ErbB2 erythroblastic leukemia viral oncogene homolog 2 -- ERK1/2 extracellular signal-regulated protein kinases 1 and 2 -- ESO esomeprazole -- GSK-3β glycogen synthase kinase-3 beta -- LAN lansoprazole -- mTOR mammalian target of rapamycin -- MTT 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- OME omeprazole -- PBS phosphate-buffered saline -- PCa prostate cancer -- PI3K phosphatidylinositol 3 kinase -- PPIs proton pump inhibitors -- PTEN phosphatase and tensin homolog -- PSA prostate-specific antigen -- SCID severe combined immunodeficient -- RT-PCR reverse transcriptase-polymerase chain reaction -- TURP transurethral resection of prostate; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.02.028
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: PPIs promote survival and growth, and inhibit apoptosis of PCa cells. PPIs elevate c-Myc expression, ErbB2 activity and PSA secretion in PCa cells. PPIs act through MAPK ERK1/2, PI3K/Akt and GSK-3β and inhibit cPAcP in PCa cells. PPIs promote the growth of PCa xenografts in vivo .