Role of HO-1, its modulation and functional significance in Prostate Cancer

GUERON GERALDINE; TURNER A; WOOD EDWARD; VAZQUEZ ELBA; USMANI A

York UK

Congreso; YCR Annual Science Meeting 2006; 2006

University of York

     Abstract        Prostate cancer (PCa) is one of the most common causes of cancer in men. It is considered a lethal malignancy with increasing incidence worldwide. Although, prostate cancer 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. 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 could possibly play a critical role in the process of prostate carcinogenesis. To better understand the role of  HO-1 in PCa, we assessed the expression of this enzyme in three PCa cell lines, PC-3 (androgen independent), LNCaP and the bone metastatic cell line PCaMDa2b (androgen dependent), observing by Western Blot analysis different expression levels, with the highest levels detected in PCaMDa2b. We further analysed the expression of this enzyme in PC3 and PCaMDa2b under inflammatory conditions, induced by 24h LPS (1ug/ml) treatment. HO-1 protein expression was time and dose dependent for both cell lines, with a striking 3-fold induction for PC-3. Hemin treatment (80 uM), a potent inducer of HO-1, revealed an up-regulation of this enzyme after 24 hours on both cell lines. When both cell lines were treated with tin protoporphyrin (SnPP IX), a selective inhibitor of HO-1 activity, similar protein profile response was detected in the presence/absence of LPS. Furthermore, cell cycle  analysis  showed  different responses leading to a Go/G1 arrest for PC3 cells under LPS and hemin treatment and a Go/G1 arrest  for PCaMDa2b  under LPS + SnPP treatment. Taken together these results are indicative of HO-1 differential expression and response to inducer/inhibitor modulation in PCa cell lines. This modulation under inflammatory conditions correlates with alteration of cell cycle regulation and may be implicated in the arrest of the metastatic cell lines.