The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappaB pathways.

Abstract

BACKGROUND:

Benign prostatic hyperplasia (BPH) is characterized by an important inflammatory component. Stimulation of human prostate stromal cells from BPH tissues with proinflammatory cytokines leads to secretion of IL-8, a chemokine involved in BPH pathogenesis. The vitamin D receptor (VDR) agonist elocalcitol can arrest prostate growth in BPH patients, but its mechanism of action in this pathology is still incompletely understood.

METHODS:

IL-8 levels were measured by real-time RT-PCR and ELISA. NF-kappaB translocation and COX-2 expression were evaluated by confocal microscopy. RhoA and Rho-kinase (ROCK) gene expression and functional activity were studied by real-time RT-PCR, immuno-kinase assays, Western blot analysis, confocal microscopy, and cell invasion.

RESULTS:

Stimulation of BPH cells with IL-8 activates the calcium-sensitizing RhoA/ROCK pathway, as demonstrated by the increased membrane translocation of RhoA and by phosphorylation of the ROCK substrate myosin phosphatase target subunit 1 (MYPT-1). In agreement with these data, C3 exoenzyme, a selective RhoA inhibitor, inhibits IL-8-induced invasion of BPH cells. The VDR agonist elocalcitol significantly inhibits IL-8 production by BPH cells stimulated with inflammatory cytokines, and IL-8-induced proliferation of BPH cells. In addition, elocalcitol inhibits IL-8-induced membrane translocation of RhoA and MYPT-1 phosphorylation in BPH cells, and inhibits dose-dependently their IL-8-dependent invasion. The inhibition induced by elocalcitol of IL-8 production by BPH cells is accompanied by decreased COX-2 expression and PGE(2) production and by arrest of NF-kappaB p65 nuclear translocation, associated with inhibition of the RhoA/ROCK pathway.

CONCLUSIONS:

These data provide a mechanistic explanation for the anti-proliferative and anti-inflammatory properties of elocalcitol in BPH cells.

• Authors: Giuseppe Penna, Benedetta Fibbi, Susana Amuchastegui, Elisa Corsiero, Gilles Laverny, Enrico Silvestrini, Aravinda Chavalmane, Annamaria Morelli, Erica Sarchielli, Gabriella Barbara Vannelli, Mauro Gacci, Enrico Colli, Mario Maggi, Luciano Adorini
• Journal: The Prostate (Prostate) Vol. 69 Issue 5 Pg. 480-93 (Apr 01 2009) ISSN: 1097-0045 [Electronic] United States
• PMID: 19107880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• BXL628
• Interleukin-17
• Interleukin-8
• NF-kappa B
• Receptors, Calcitriol
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Cyclooxygenase 2
• rho-Associated Kinases
• rhoA GTP-Binding Protein
• Calcitriol
• Dinoprostone

Topics

• Calcitriol (analogs & derivatives, pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclooxygenase 2 (metabolism)
• Dinoprostone (metabolism)
• Humans
• Inflammation (metabolism, pathology)
• Interferon-gamma (pharmacology)
• Interleukin-17 (pharmacology)
• Interleukin-8 (metabolism)
• Male
• NF-kappa B (metabolism)
• Prostatic Hyperplasia (metabolism, pathology)
• Receptors, Calcitriol (agonists)
• Signal Transduction (drug effects)
• Stromal Cells (metabolism, pathology)
• Tumor Necrosis Factor-alpha (pharmacology)
• rho-Associated Kinases (metabolism)
• rhoA GTP-Binding Protein (metabolism)