HO-1 challenges the epithelial mesenchymal transition in prostate cancer

GUERON G; SALLES A; LABANCA E; COLLUCCIO-LESKOW F; NAVONE N; DE SIERVI A; VAZQUEZ E

USA

Congreso; 102nd Annual Meeting American Association for Cancer Research; 2011

American Association for Cancer Research

Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Tumorigenesis is highly associated with inflammation. Key mediators of this event may play multiple roles in the etiology of PCa and the onset of its progression. The metastatic spread of PCa cells relies on their ability to undergo EMT acquiring undifferentiated properties, loosing the tight junctions between them, hence becoming more motile and invasive. In this context, heme oxygenase-1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, emerges as a potential epithelial mesenchymal transition (EMT) modulator counteracting oxidative and inflammatory damage. Here we assessed the expression profile of the EMT markers and the interplay between EMT regulators in androgen sensitive (MDAPCa2b and LNCaP) and insensitive (PC3) PCa cell lines under HO- 1 modulation. Our results show that treatment with hemin, a potent and specific inducer of HO-1, increased mRNA levels of Ecadherin, !-catenin, and endoglin. Stable transfection of HO-1 in PC3 (PC3HO-1) also showed a significant increase of these epithelial markers. PC3HO-1 xenografts growing subcutaneously in athymic nude mice showed significant up-regulation of these markers compared to control tumours. Furthermore, using an RT-qPCR-generated gene array we identified the adhesion molecule COL4A3 as a novel downstream target of HO-1. HO-1 modulation limited the metastatic potential of neoplastic cells by upregulating COL4A3 production. Moreover, a quantitative analysis of cell adhesive forces revealed that HO-1 induction increased PCa cell adhesion to a collagen IV matrix. Taken together these results implicate for the first time HO-1 in the modulation of the EMT and cell adhesion in PCa progression. Targeting EMT program directly or indirectly through HO-1 modulation may represent a novel avenue to decrease tumor bulk and eradicate undifferentiated cells with potential to colonize a rare field. epithelial markers. PC3HO-1 xenografts growing subcutaneously in athymic nude mice showed significant up-regulation of these markers compared to control tumours. Furthermore, using an RT-qPCR-generated gene array we identified the adhesion molecule COL4A3 as a novel downstream target of HO-1. HO-1 modulation limited the metastatic potential of neoplastic cells by upregulating COL4A3 production. Moreover, a quantitative analysis of cell adhesive forces revealed that HO-1 induction increased PCa cell adhesion to a collagen IV matrix. Taken together these results implicate for the first time HO-1 in the modulation of the EMT and cell adhesion in PCa progression. Targeting EMT program directly or indirectly through HO-1 modulation may represent a novel avenue to decrease tumor bulk and eradicate undifferentiated cells with potential to colonize a rare field. -catenin, and endoglin. Stable transfection of HO-1 in PC3 (PC3HO-1) also showed a significant increase of these epithelial markers. PC3HO-1 xenografts growing subcutaneously in athymic nude mice showed significant up-regulation of these markers compared to control tumours. Furthermore, using an RT-qPCR-generated gene array we identified the adhesion molecule COL4A3 as a novel downstream target of HO-1. HO-1 modulation limited the metastatic potential of neoplastic cells by upregulating COL4A3 production. Moreover, a quantitative analysis of cell adhesive forces revealed that HO-1 induction increased PCa cell adhesion to a collagen IV matrix. Taken together these results implicate for the first time HO-1 in the modulation of the EMT and cell adhesion in PCa progression. Targeting EMT program directly or indirectly through HO-1 modulation may represent a novel avenue to decrease tumor bulk and eradicate undifferentiated cells with potential to colonize a rare field.