TRAIL receptor 1 (DR4) is frequently methylated in ovarian cancer: Relevance for TRAIL sensitivity and ovarian cancer tumorigenesis

2500 Introduction. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a type II transmembrane protein of the TNF family. It can be cleaved from the membrane into its soluble form and bind the apoptosis activating receptors DR4 and DR5. In ovarian cancer, elevated TRAIL expression is associated with favorable overall survival suggesting a crucial role of this apoptotic pathway in ovarian cancer pathology. Methods. We used a tissue microarray to immunohistochemically assess the expression of TRAIL and its receptors on tumor cells. Additionally, expression of DR4 was measured by qRT-PCR. Methylation specific PCR was employed to study the epigenetic modulation of DR4 in primary ovarian cancer. To assess the functional relevance of DR4 expression, we performed demethylation, DR4 overexpression and DR4 siRNA experiments in TRAIL resistant and TRAIL sensitive ovarian cancer cell lines. Results. The analysis of the tissue microarray revealed a correlation of elevated DR4 expression with grading (r= 0.501, p