TY - JOUR
T1 - Activity-dependent COX-2 proteolysis modulates aerobic respiration and proliferation in a prostaglandin-independent manner
AU - Hartal-Benishay, Liat Hagit
AU - Tal, Sharon
AU - Elkader, Amal Abd
AU - Ehsainieh, Omar
AU - Srouji-Eid, Ranin
AU - Lavy, Tali
AU - Kleifeld, Oded
AU - Mikl, Martin
AU - Barki-Harrington, Liza
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024/12/20
Y1 - 2024/12/20
N2 - 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.
AB - 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.
KW - Biomolecules
KW - Molecular biology
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85210285215&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.isci.2024.111403
DO - https://doi.org/10.1016/j.isci.2024.111403
M3 - Article
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 12
M1 - 111403
ER -