Celecoxib Reduces Colon Cancer by Inactivating Enzymes That Block Apoptosis

A recent publication outlined the molecular mechanism by which the anti-inflammatory drug celecoxib acts to reduce the risk of colon cancer.

Celecoxib is a COX-2 inhibitor of the nonsteroidal anti-inflammatory drugs (NSAID) class that is used to relieve pain and inflammation in the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. In addition, celecoxib has been shown to reduce the risk of developing colon cancer. However, some studies have suggested that long-time use of celecoxib increases risk of developing cardiovascular disease.

In the current study, investigators at Emory University (Atlanta, GA, USA) defined a mechanism for celecoxib action based on degradation of the protein c-FLIP (CASP8 and FADD-like apoptosis regulator), a major regulator of the apoptosis receptor pathway.

They reported in the August 25, 2011, online edition of the journal Cancer Research that celecoxib inhibited the enzyme GSK3 (glycogen synthase kinase 3). GSK-3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates. The phosphorylation of these other proteins by GSK-3 usually inhibits the target protein.

Celecoxib was found to increase the levels of phosphorylated GSK3, which resulted in lowering the level of c-FLIP. With fewer molecules of c-FLIP to block the apoptosis pathways, cells died instead of transforming into cancer cells.

“We have been focusing on how celecoxib induces c-FLIP degradation and apoptosis in cancer cells, independent of COX-2 inhibition,” said senior author Dr. Shi-Yound Sun, professor of hematology and medical oncology at Emory University. “However, we do not know whether GSK3 inhibition by celecoxib has anything to do with celecoxib’s cardiovascular risk.”

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