HO-1: THE MASTERMIND BEHIND THE MORPHOLOGY AND THE ADHESIVE BEHAVIOR OF PROSTATE CANCER CELLS

GUERON G; GIUDICE J; VALACCO P; ELGUERO B; PAEZ A; TOSACANI M; JAWORSKI F; COLLUCCIO-LESKOW F; COTIGNOLA J; MARTÍ M; BINAGHI M; NAVONE N; VAZQUEZ E

Maryland

Congreso; Prostate Cancer Foundation Annual Retreat 2013; 2013

Prostate Cancer Foundation

Background: Prostate Cancer (PCa) is the second leading cause of cancer death in American men. The loss of cell-cell adhesion is frequently associated with the progression to a metastatic state. Although previous studies about cell adhesion in PCa have focused on adherens junctions (AJs), key players in the integrity of the epithelium, they have left the molecular mechanisms unexplored. Heme Oxygenase-1 (HO-1) acts as a cellular rheostat counteracting oxidative and inflammatory damage1. We previously showed that HO-1 over-expression impaired tumor growth and angiogenesis in vivo. Given that inflammation is critical for the development and progression of PCa, we assessed whether HO-1 could regulate the adhesive properties and the morphology of PCa cells. Methods: GeneMANIA5, DAVID and Metacore were used as bioinformatics tools. Immunofluorescence analyses and quantitative microscopy were done as previously described. GST-pull-down assays were performed using lysates from PC3 cells transfected with either GST-tagged HO-1 or the empty vector, and the isolated proteins were subjected to MALDI-TOF/TOF analyses. Results: Genes differentially regulated by HO-1 were enriched for cell motility and adhesion biological processes. Induction of HO-1 increased cell adhesion and E-cadherin/β-catenin levels, the main cell adhesion molecules at AJs8. Furthermore, a striking remodeling of E-cadherin/β-catenin-based AJs was also observed, consistent with a marked change in cell morphology. In an effort to understand the molecular mechanisms underlying HO-1?s role in cell morphology regulation we used a proteomics approach to identify HO-1 partners. Our results showed that HO-1 interacts with Muskelin9, which has been strongly implicated in cell morphology regulation. Conclusion: These results define a novel role for HO-1 in modulating the architecture of cell-to-cell interactions, favoring a less aggressive phenotype and further supporting its anti-tumoral function in PCa.