INVESTIGADORES
DE SIERVI Adriana
congresos y reuniones científicas
Título:
Heme Oxygenase 1 (HO-1): A novel protein in prostate cancer cell proliferation, migration and invasion.
Autor/es:
GUERON G; FERRANDO M; DE LUCA P; NAVONE N; DE SIERVI A; VAZQUEZ E
Lugar:
San Diego, California, USA
Reunión:
Congreso; 99th AACR Annual Meeting; 2008
Institución organizadora:
American Association for Cancer Research
Resumen:
Prostate cancer (PCa) is considered the third leading cause of cancer death among men. However because of the complexity of this disease, PCa target genes have been difficult to identify. Recently it has been recognized that inflammation collaborates with PCa tumorigenesis. Heme oxygenases are the rate-limiting enzymes in heme degradation. Human heme oxygenase 1 (HO-1) is induced during hypoxia, ischemia/reperfusion, and inflammation. It is becoming more apparent that HO-1 activity not only provides protection in oxidative injury, but is also involved in direct modulation of the infiltrating inflammatory cells. To assess HO-1 role in PCa, we first study HO-1 protein expression levels in different PCa cell lines. Androgen independent cells (PC3) showed very low basal levels in comparison with androgen sensitive cell lines (MDA PCa2b and LNCaP). Moreover, hemin (70 µM, 24h), a known HO-1 inducer, increased HO-1 protein and mRNA expression levels in those cell lines. Accordingly, HO-1 promoter activity was increased by hemin and ARE (anti-oxidant response element) mutation sites totally abolished this induction in PCa cell lines. Furthermore, treatment of PCa cell cultures with hemin resulted in a 23% and 45% (p<0.05) reduction in cell proliferation in PC3 and MDA PCa2b, respectively. Interestingly, over-expression of HO-1 levels in stable transfected PC3 cells showed a significant reduction in cell proliferation. To understand more about HO-1 role in PCa, we further investigated migration (wound healing assay) and invasion (Matrigel invasion chambers) after pharmacologic and genetic modulation of HO-1 protein levels. A marked inhibition in cell migration and invasion was observed under HO-1 induction in the androgen independent cell line. Strikingly, MDA PCa2b cells, with higher HO-1 endogenous expression levels, showed no migratory ability. To identify key genes in HO-1 mediated migration/invasion process, RT-qPCR of 113 related genes showed that MDA PCa2b cells with higher HO-1 levels have very low levels of CXC inflammatory chemokines, whereas PC3 produce greater amounts. Surprisingly, CXCL3 was markedly down-regulated by hemin treatment in PC3 cells. Taken together, these results show that HO-1 is directly implicated in the migration and invasion of prostate cancer cells, providing an emerging target in the progression of this disease.