γ-Tocotrienol induces apoptosis in pancreatic cancer cells by upregulation of ceramide synthesis and modulation of sphingolipid transport

BMC Cancer
Victoria E PalauKoyamangalath Krishnan

Abstract

Ceramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport. The effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells. Quantitative changes in ceramides, dihydroceramides, and sphingomyelin at the cell membrane were detected by LCMS. Modulation of ceramide transport by GT3 was studied by immunochemistry of CERT and ARV-1, and the subsequent effects at the cell membrane was analyzed via immunofluorescence of ceramide, caveolin, and DR5. GT3 favors the upregulation of ceramide by stimulating synthesis at the ER and the plasma membrane. Additionally, the conversion of newly synthesized ceramide to sphingomyelin and glucosylceramide at th...Continue Reading

References

Nov 7, 1998·The Journal of Biological Chemistry·S BasuR Kolesnick
Apr 14, 1999·Cell Death and Differentiation·A P BrunoJ P Jaffrézou
Nov 7, 2000·The Journal of Biological Chemistry·A H TinkelenbergS L Sturley
Nov 14, 2000·The American Journal of Pathology·H OuyangM S Tsao
Feb 24, 2001·The Journal of Pharmacy and Pharmacology·S P YapJ W Wong
Mar 30, 2001·The Journal of Biological Chemistry·Y ZhangZ Dong
Mar 30, 2001·The Journal of Biological Chemistry·H GrassmeE Gulbins
Mar 21, 2002·Nature Reviews. Cancer·P MarksW K Kelly
Jul 30, 2002·The Journal of Biological Chemistry·Evelyn SwainJoseph T Nickels
Feb 1, 2003·The Biochemical Journal·Norman S Radin
Mar 20, 2003·Journal of Neuroscience Research·John KilkusGlyn Dawson
May 29, 2003·Biochimie·G TettamantiL Riboni
Dec 20, 2003·Nature·Kentaro HanadaMasahiro Nishijima
May 20, 2004·Cancer Research·Sandrine LacourMarie-Thérèse Dimanche-Boitrel
Dec 15, 2004·Proceedings of the National Academy of Sciences of the United States of America·Qing JiangBruce N Ames
Mar 17, 2005·The Journal of Biological Chemistry·Alexandra CharruyerJean-Pierre Jaffrézou
Apr 13, 2005·The Biochemical Journal·Yukiko MizutaniYasuyuki Igarashi
Jul 13, 2005·The Journal of Experimental Medicine·Michihiko MiyajiHisanori Umehara
Aug 15, 2006·The Journal of Biological Chemistry·Fikadu Geta TafesseJoost C M Holthuis
Nov 24, 2007·Biochimica Et Biophysica Acta·Valérie Gouazé-AnderssonMyles C Cabot
Feb 25, 2010·FEBS Letters·Branka Stancevic, Richard Kolesnick
Sep 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·Peter NagyDonna J Arndt-Jovin
Feb 8, 2011·CA: a Cancer Journal for Clinicians·Ahmedin JemalDavid Forman

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Citations

Feb 6, 2019·International Journal of Molecular Sciences·Vaishali AggarwalMukerrem Betul Yerer
Mar 15, 2019·International Journal of Molecular Sciences·Kai Dun TangMing-Tat Ling
Dec 29, 2019·Scientific Reports·Tejia ZhangRandall T Peterson
Oct 18, 2019·Journal of Nutritional Science and Vitaminology·Shinji YamashitaTeruo Miyazawa
Jun 18, 2019·Current Computer-aided Drug Design·Nurul Syeefa ZulkifleeTan Jen Kit
Dec 18, 2020·Frontiers in Molecular Biosciences·Mariem GhoulaOlivier Taboureau
Aug 24, 2019·Progress in Lipid Research·Sebastian BrachtendorfSabine Grösch
Nov 23, 2021·Frontiers in Nutrition·Keri BarronNatalia Krupenko

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Methods Mentioned

BETA
protein assay
confocal microscopy
oncotherapy

Software Mentioned

Leica
GraphPad Prism
LSM

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