Abstract
Although p53-inactivating mutations have been described in the majority of human cancers, their role in prostate cancer is controversial as mutations are uncommon, particularly in early lesions. p53 is activated by hypoxia and other stressors and is primarily regulated by the Mdm2 protein. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and other eicosanoids, is also induced by hypoxia. COX-2 and resultant prostaglandins increase tumor cell proliferation, resistance to apoptosis, and angiogenesis. Previous reports indicate a complex, reciprocal relationship between p53 and COX-2. To elucidate the effects of COX-2 on p53 in response to hypoxia, we transfected the COX-2 gene into the p53-positive, COX-2-negative MDA-PCa-2b human prostate cancer cell line. The expression of functional p53 and Mdm2 was compared in COX-2+ versus COX-2- cells under normoxic and hypoxic conditions. Our results demonstrated that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in these cells. Forced expression of COX-2 increased tumor cell viability and decreased apoptosis in response to hypoxia. COX-2+ cells had increased Mdm2 phosphorylation in either normoxic or hypoxic conditions. Overexpression of COX-2 abrogated hypoxia-induced p53 phosphorylation and promoted the binding of p53 to Mdm2 protein in hypoxic cells. In addition, COX-2-expressing cells exhibited decreased hypoxia-induced nuclear accumulation of p53 protein. Finally, forced expression of COX-2 suppressed both basal and hypoxia-induced p53 transcriptional activity, and this effect was mimicked by the addition of PGE2 to wild-type cells. These results demonstrated a role for COX-2 in the suppression of hypoxia-induced p53 activity via both direct effects and indirect modulation of Mdm2 activity. These data imply that COX-2-positive prostate cancer cells can have impaired p53 function even in the presence of wild-type p53 and that p53 activity can be restored in these cells via inhibition of COX-2 activity.
Highlights
The p53 tumor suppressor protein plays a critical role in the regulation of cell growth, the protection of normal cells from malignant transformation, and the response of tumor cells to radiation and chemotherapy [1, 2]
We reported that COX-2 and PGE2 are key mediators of cellular responses observed after hypoxia resulting from induction of vascular endothelial cell factor [12, 19] and the master oxygen sensor, hypoxia-inducible factor (HIF)-1␣ [20]
Hypoxia Induces COX-2 Expression in COX-2-transfected MDA-PCa-2b Cells—It has been reported that COX-2 expression is increased by hypoxia and cobalt chloride in human vascular endothelial cells and a metastatic prostate cancer cell line, respectively [11, 12]
Summary
The p53 tumor suppressor protein plays a critical role in the regulation of cell growth, the protection of normal cells from malignant transformation, and the response of tumor cells to radiation and chemotherapy [1, 2]. Our results demonstrated that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in these cells. Overexpression of COX-2 abrogated hypoxia-induced p53 phosphorylation and promoted the binding of p53 to Mdm2 protein in hypoxic cells.
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