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

Iacopo Gesmundo, Laura Di Blasio, Dana Banfi, Tania Villanova, Alessandro Fanciulli, Enrica Favaro, Giacomo Gamba, Chiara Musuraca, Ida Rapa, Marco Volante, Stefania Munegato, Mauro Papotti, Paolo Gontero, Luca Primo, Ezio Ghigo, Riccarda Granata

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)252-262
Number of pages11
JournalCancer Letters
Volume449
DOIs
Publication statusPublished - May 1 2019

Keywords

  • Acid Phosphatase/antagonists & inhibitors
  • Animals
  • Apoptosis/drug effects
  • Cell Proliferation/drug effects
  • Glycogen Synthase Kinase 3 beta/metabolism
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitogen-Activated Protein Kinase 1/metabolism
  • Mitogen-Activated Protein Kinase 3/metabolism
  • Neoplasms, Hormone-Dependent/enzymology
  • Omeprazole/toxicity
  • PC-3 Cells
  • Phosphatidylinositol 3-Kinase/metabolism
  • Phosphorylation
  • Prostatic Neoplasms/enzymology
  • Proto-Oncogene Proteins c-akt/metabolism
  • Proton Pump Inhibitors/toxicity
  • Receptor, ErbB-2/metabolism
  • Signal Transduction

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  • Cite this

    Gesmundo, I., Di Blasio, L., Banfi, D., Villanova, T., Fanciulli, A., Favaro, E., Gamba, G., Musuraca, C., Rapa, I., Volante, M., Munegato, S., Papotti, M., Gontero, P., Primo, L., Ghigo, E., & Granata, R. (2019). 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. Cancer Letters, 449, 252-262. https://doi.org/10.1016/j.canlet.2019.02.028