Gynecologic Oncology & Preventive Oncology

Biography

Biography: Qing Jiang

Abstract

Gamma-tocotrienol (γTE) is a vitamin E form rich in palm oil.  Gamma-tocotrienol has been shown to be stronger than vitamin E tocopherols in inducing death of cancer cells, and therefore proposed to be a potentially useful chemopreventive agent.  However, mechanisms underlying these actions are not clear.  Here using liquid chromatography tandem mass spectrometry, we show that γTE induced marked changes of sphingolipids including rapid elevation of dihydrosphingosine and dihydroceramides (dhCers) in various types of cancer cells.  The elevation of dihydrosphingolipids coincided with increased cellular stress, as indicated by JNK phosphorylation, and was prior to any sign of induction of apoptosis.  Chemically blocking de novo synthesis of sphingolipids partially counteracted gTE-induced apoptosis and autophagy.  Experiments using ¹³C₃, ¹⁵N-labeled l-serine together with enzyme assays indicate that γTE inhibited cellular dihydroceramide desaturase (DEGS) activity without affecting its protein expression or de novo synthesis of sphingolipids.  Unlike the effect on dhCers, γTE decreased ceramides (Cers) after 8 h treatment, but increased C_18:0-Cer and C_16:0-Cer after 16 and 24 h, respectively.  The increase of Cers coincides with gTE-induced apoptosis and autophagy.  Since gTE inhibits DEGS and decreases de novo Cer synthesis, elevation of Cers during prolonged gTE treatment is likely caused by sphingomeylinase-mediated hydrolysis of sphingomyelin.  This idea is supported by the observation that an acid sphingomeylinase inhibitor partially reversed gTE-induced cell death.  Our study demonstrates that γTE altered sphingolipid metabolism by inhibiting DEGS activity and possibly by activating SM hydrolysis during prolonged treatment in cancer cells.