The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Sphingolipids, including ceramides (Cers), are crucial in regulating cell proliferation, apoptosis, and cell cycle.
• Elevated Cer levels are associated with the cytotoxic actions of chemotherapeutics.
• Selective cyclooxygenase-2 (COX-2) inhibitors, known as coxibs, exhibit anti-proliferative effects on tumor cells.

Purpose of the Study:

• To investigate the potential interaction between selective COX-2 inhibitors (coxibs) and the sphingolipid pathway.
• To elucidate the role of sphingolipid pathway modulation in the anti-proliferative effects of coxibs.

Main Methods:

• Measurement of sphingolipids using liquid chromatography tandem mass spectrometry.
• Treatment of cancer cell lines with celecoxib and other coxibs.
• Utilizing (13)C,(15)N-labeled l-serine to trace de novo synthesis.
• Inhibition of dihydroceramide desaturase (DEGS) and sphingolipid biosynthesis.

Main Results:

• Celecoxib treatment increased sphinganine and dihydroceramides (dhCers) while depleting ceramides (Cers) in a time- and concentration-dependent manner.
• Other coxibs did not show similar effects on sphingolipid profiles.
• Celecoxib inhibited DEGS in vitro (IC(50) = 78.9 muM) and increased total Cer levels, indicating activation of sphingolipid biosynthesis.
• Inhibition of sphingolipid biosynthesis attenuated the anti-proliferative potency of celecoxib.

Conclusions:

• Celecoxib's anti-proliferative effects are partly mediated by inducing de novo sphingolipid synthesis.
• Celecoxib's inhibition of DEGS contributes to its anti-proliferative activity.
• The sphingolipid pathway is a key target for celecoxib's anti-cancer actions.