Activity-dependent COX-2 Proteolysis Modulates Aerobic Respiration and Proliferation in a Prostaglandin-independent Manner

Overview

Journal iScience

Publisher Cell Press

Date 2024 Dec 17

PMID 39687029

Authors

Liat Hagit Hartal-Benishay

Sharon Tal

Amal Abd Elkader

Omar Ehsainieh

Ranin Srouji-Eid

Tali Lavy

Oded Kleifeld

Martin Mikl

Liza Barki-Harrington

Affiliations

Soon will be listed here.

Abstract

Cyclooxygenase-2 (COX-2) catalyzes the oxidation of arachidonic acid (AA) into a single product that is the source of all prostaglandins (PGs), ligands of multiple pro-inflammatory pathways. AA catalysis results in suicide inactivation, rendering the enzyme catalytically inactive. Here, we report that 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 find COX-2 fragments in human colon tumors. Using mass spectrometry, we identified 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. Expression of one of these fragments in cells significantly reduced mitochondrial function, increased lactate production, and enhanced proliferation. We propose that in addition to its role in generating PGs, COX-2 has PG-independent cellular functions that may account for its complex role in proliferative diseases and chronic inflammation.

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