Abstract 207: Rearrangements of the E-cadherin/B-catenin-based adherens junctions caused by forced-expression of heme oxygenase 1 (HO-1) in prostate cancer.

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Prostatic tumor cell plasticity involves cooperative changes in the interactions between tumoral cells. The stable E-cadherin-based Adherence Junctions (AJs) play a pivotal role in the integrity of the epithelium and the maintenance of tissue homeostasis. Heme oxygenase-1 (HO-1) acts as a cell rheostat counteracting oxidative and inflammatory damage. Given that inflammation is critical for the development and progression of PCa, we sought to determine whether HO-1 could regulate the adhesive properties of PCa cells, towards the acquisition of an epithelial-like phenotype. We previously showed that HO-1 over-expression impairs tumor growth and represses angiogenesis in vivo. Here we demonstrate that HO-1 over-expression significantly increased PCa cell adhesion, remodeling the AJs. To better understand the nature of alterations of cell-cell interactions during neoplastic evolution, we examined the expression levels of E-cadherin and B-catenin. Treatment with hemin, a potent and specific inducer of HO-1, increased E-cadherin and b-catenin protein and mRNA levels in PCa cell lines, shown by Western Blot, RT-qPCR and flow cytometry analyses. These epithelial markers were also significantly induced when PCa cells were stably transfected with HO-1. Immunofluorescence, confocal microscopy together with a three-dimensional (3D) acquisition process leading to the collection of image stacks, confirmed the augmented levels of these proteins under forced-expression of HO-1 and also revealed a striking rearrangement of their localization pattern towards the cell membrane. Moreover, quantitative image analysis detected a significant increase in the percentage of cell-to-cell contact among tumoral cells under HO-1 overexpression. The enhanced levels of E-cadherin and B-catenin in PCa cells under hemin treatment coincided with a markedly different morphology compared to untreated cells, observed by bright field microscopy. While untreated cells displayed an elongated and fibroblastic-like shape, with increased number of lamellipodia, HO-1-overexpressing cells showed a spherical cobblestone epithelial shape. These results define a novel role for HO-1 in modulating the cellular morphology and the architecture of cell-to-cell interactions, favoring a less aggressive phenotype and further supporting its anti-tumoral function in PCa. Citation Format: Geraldine Gueron, Belen Elguero, Alejandra Paez, Jimena Giudice, Martin Toscani, Felipe Jaworski, Daiana Leonardi, Federico Coluccio-Leskow, Adriana De Siervi, Nora Navone, Elba Vazquez. Rearrangements of the E-cadherin/B-catenin-based adherens junctions caused by forced-expression of heme oxygenase 1 (HO-1) in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 207. doi:10.1158/1538-7445.AM2013-207