Heme oxygenase 1 (HO-1): an emerging target in prostate cancer

GUERON G; DE SIERVI A; VAZQUEZ E

Los Angeles, California, USA

Congreso; 98th AACR Annual Meeting; 2007

American Association for Cancer Research

Prostate cancer (PCa) is one of the most common cancers in men. It is considered a lethal malignancy with increasing incidence worldwide. Although PCa progression is well characterized by the androgen resistant phenotype, little is known about the genetic events of the malignant transformation. Androgen deprivation induces changes in the phenotype of PCa followed by alterations in protein expression. Recent evidence has suggested that proliferative inflammatory atrophy is a precursor of prostatic intraepithelial neoplasia and PCa. Heme Oxygenase 1 (HO-1) the inducible isoform of the rate-limiting enzyme in the degradation of heme, could counteract immune-mediated injury either through prevention of oxidative damage or via a local immunomodulatory influence on infiltrating inflammatory cells. Due to the key role that inflammation plays in the development of the tumor and subsequent metastasis, we hypothesize that modulation of HO-1 expression plays a critical role in PCa progression. To better understand the role of HO-1 in PCa, we assessed the expression of this enzyme in PCa cell lines. Western Blot analysis revealed low basal levels in the androgen independent cell line PC3 compared to androgen sensitive cell lines (LNCaP and MDA PCa 2b). We further analyzed HO-1 modulation effect on cell proliferation (3H-incorporation) and invasion (Matrigel invasion chambers). Treatment of PC3 cell cultures with hemin (70 µM, 24h), a potent inducer of HO-1, resulted in a 20% (p<0.05) reduction in cell proliferation and a 68% inhibition in cell invasion (p<0.001). Accordingly, tin protoporphyrin (SnPP, 10 µM), an inhibitor of HO-1 activity, increased cell proliferation by 50% (p<0.05) and cell invasion by 20% (p<0.001). These results implicate HO-1 as a mediator of PCa proliferation and invasion in androgen independent prostate cancer and could offer a novel therapeutic target for this disease.