HO-1 in prostate cancer bone progression

FERRANDO M; GUERON G; DE LUCA P; DE SIERVI A; VAZQUEZ E

Miami, USA

Congreso; Heme Oxygenases in Biology & Medicine; 2009

Prostate cancer (PCa), one of the most common cancers among men, is dominated by complications arising from bone metastases and PCa is the only malignancy that consistently produces osteoblastic metastases to the bone.  Vascular endothelial growth factor (VEGF) was involved in the pathophysiology of PCa bone metastasis. We recently demonstrated that heme oxygenase 1 (HO-1), a key protein in the control of inflammation, is associated with prostate carcinogenesis. The aim of this study was to evaluate the role of HO-1 in the regulation of genes involved in PCa metastasis. Human PCa cell lines, LNCaP and PC3 (androgen sensitive and insensitive, respectively) were treated with hemin (80µM, 24h) producing a significantly induction of HO-1 mRNA levels in both cell lines. Under HO-1 upregulation, we analyzed the expression of markers of bone metastases (metalloproteinase 9 (MMP9) and osteopontin (OPN)) and of angiogenesis and linfoangiogenesis (VEGF-C and VEGF-A, respectively). In PC3 cells, hemin treatment significantly increased VEGF-A expression, whereas pharmacological induction of HO-1 in LNCaP decreased MMP9, OPN and VEGF-C expression. Using reporter genes, we also demonstrated HO-1 regulates the activity of VEGF-A promoter. In addition, we found that LNCaP has higher basal levels of VEGF-A and VEGF-C, while PC3 has higher basal levels of OPN and MMP9. Furthermore, hemin treatment increased the expression of PSA (prostate specific antigen) in androgen sensitive cells, which might reflect a shift towards a greater degree of cell differentiation. All these results suggest that HO-1 overexpression could be associated with a less aggressive phenotype in prostate cancer.