Activity-dependent COX-2 proteolysis generates a catalytically inactive fragment that affects aerobic respiration and proliferation

Cyclooxygenase-2 (COX-2) catalyzes arachidonic acid (AA) into PGH2, the single source of all prostaglandins (PGs), ligands that activate multiple inflammatory pathways. AA catalysis quickly results in suicide inactivation, rendering the enzyme catalytically inactive. We show that the catalytic activity also leads to controlled cleavage of COX-2, an event that is differentially regulated by fatty acids, and blocked by COX inhibitors. We also observe COX-2 cleavage in human colon tumors. Using mass spectrometry, we identify two adjacent cleavage points within the catalytic domain, which give rise to COX-2 fragments that are catalytically inactive and localize to different cellular compartments. One of these fragments significantly alters the expression of mitochondrial electron transport genes and functional assays show that it leads to reduced mitochondrial function, increased lactate production, and enhanced proliferation. We propose that in addition to its role in generating PGs, COX-2 has subsequent PG-independent cellular functions that may account for the complex role of COX-2 in proliferative diseases and chronic inflammation.