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

• Published in: Cancer letters 2019-05, Vol.449, p.252-262
• Main 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
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acid phosphatase; Acid Phosphatase - antagonists & inhibitors; Acid Phosphatase - metabolism; Acids; AKT protein; Androgens; Animals; Apoptosis; Apoptosis - drug effects; c-Myc protein; Cancer therapies; Castration; Cell culture; Cell cycle; Cell proliferation; Cell Proliferation - drug effects; Cellular prostatic acid phosphatase; Colorectal cancer; Disease; Epithelial cells; ErbB-2 protein; Extracellular signal-regulated kinase; Gastroesophageal reflux; Glycogen Synthase Kinase 3 beta - metabolism; Health risks; Humans; Hyperplasia; Inhibitors; Kinases; Leukemia; Male; MAP kinase; Mesothelioma; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myc protein; Neoplasms, Hormone-Dependent - enzymology; Neoplasms, Hormone-Dependent - pathology; Omeprazole; Omeprazole - toxicity; Pancreatic cancer; PC-3 Cells; Penicillin; Phosphatase; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Primary prostate epithelial cells; Prostate cancer; Prostate cancer cells; Prostate specific antigen; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Proton pump inhibitors; Proton Pump Inhibitors - toxicity; Receptor, ErbB-2 - metabolism; Secretion; Signal Transduction; Survival; Tumors; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.02.028

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. •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.