title: γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death.
abstract: The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.
authors.affiliation: School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.|School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.
authors.forename: Roshan V
authors.initials: RV
authors.lastname: Tiwari
authors.affiliation: School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.|School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.
authors.forename: Parash
authors.initials: P
authors.lastname: Parajuli
authors.affiliation: School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.|School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe LA 71209, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002839:Chromans; D005456:Fluorescent Dyes; D014810:Vitamin E; C013649:plastochromanol 8
keywords: apoptose; apoptosis; autophagie; autophagy; breast cancer; cancer du sein; endoplasmic reticulum stress; stress du réticulum endoplasmique; γ-tocotrienol; γ-tocotriénol