A catalytically-independent role for cyclooxygenase-2 in cell proliferation

Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme that converts arachidonic acid (AA) into a single intermediate that gives rise to all prostanoids- central mediators of inflammation. Elevated COX-2 expression is a hallmark of many malignancies, where its expression strongly correlates with poor prognosis. However, multiple clinical trials repeatedly fail to show any advantage in the use of COX-2 inhibitors on patient survival. We propose a shift in this paradigm by hypothesizing that COX-2 has a second, activity-independent role in cell proliferation. First, we show that several types of tumors with COX-2 overexpression present with multiple COX-2 immunoreactive fragments. Furthermore, prolonged exposure of COX-2 to AA, leads to loss of enzymatic activity and to controlled cleavage of the protein by specific proteases. Cloning and expression of two such fragments identified by mass spectrometry resulted in significant changes in proliferation rate. A subsequent transcriptome and proteome analysis showed a specific effect on several cellular pathways linked with cell division. Based on our findings we propose that cleavage of COX-2 may play a novel role as a modifier of disease progression and that our research can devise new means of treating COX-2 overexpressing malignancies.