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Lipodomic analysis reveals that gamma‐tocotrienol exerts anticancer effects by inhibition of dihydroceramide desaturase and activation of sphingomyelin hydrolysis (260.6)
Author(s) -
Jang Yumi,
Jiang Qing
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.260.6
Subject(s) - sphingolipid , sphingomyelin , ceramide , chemistry , tocotrienol , sphingosine , apoptosis , endogeny , fenretinide , in vitro , biosynthesis , autophagy , biochemistry , anandamide , enzyme , vitamin e , tocopherol , cholesterol , retinoid , antioxidant , receptor , retinoic acid , gene , cannabinoid receptor , agonist
Our previous studies suggest that gamma‐tocotrienol (γTE), a vitamin E form rich in palm oil, has potent anticancer activities in cancer cells via modulation of sphingolipid metabolism. Here employing liquid chromatography tandem mass spectrometry, we investigated temporal changes of sphingolipid by γTE treatment in human colon cancer HCT‐116 cells. Incubation with γTE for 2 h resulted in accumulation of dihydrosphingosine and dihydroceramides (dhCer), and these changes intensified during prolonged treatment. In contrast, γTE treatment led to significant decrease in C 16:0 ‐ceramide (Cer) from 2 to 8 h, but showed no difference at 16 h or increase at 24 h, compared with controls. Meanwhile, γTE led to decrease in C 24:1 ‐Cer and C 24:0 ‐Cer from 6 to 24 h, but increase in C 18:0 ‐Cer from 16 h. Interestingly, sphingomyelins (SM) declined from 8 h but cells showed obvious apoptosis (PARP cleavage) or autophagy (LC3 increase) only at 16 h or longer treatment with γTE. With 13 C 3 , 15 N‐labeled L‐serine, we further evaluated the effect of γTE on de novo sphingolipid. We observed that γTE had no effect on total de novo sphingolipid biosynthesis, while induced increases in labeled dhCer, dhSM and SM, but decreases in labeled Cers and sphingosine, during 2‐6 h. These data indicate that γTE may inhibit dhCer desaturase (DEGS). Consistently, γTE inhibited the DEGS activity as indicated in situ and in vitro assays. Moreover, the decrease in endogenous SM without affecting de novo SM suggests that SM hydrolysis likely occurred. Studies are undertaken to evaluate the role of SM hydrolysis in γTE‐induced anticancer effects. These results indicate that γTE modulates enzyme activities in sphingolipid metabolism, which play roles in regulating cell death. Grant Funding Source : Supported by grants R21 CA152588 and R01AT006882 from National Institutes of Health