title: Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells.
abstract: Gamma-tocotrienol (γ-T3) is a member of the vitamin E family. Tocotrienols (T3s) are powerful antioxidants and possess anticancer, neuroprotective and cholesterol-lowering properties. Tocotrienols inhibit the growth of various cancer cell lines without affecting normal cells. Less is known about the exact mechanisms of action of T3s on cell death and other growth inhibitory pathways. In the present study, we demonstrate that γ-T3 induces apoptosis in MDA-MB 231 and MCF-7 breast cancer cells as evident by PARP cleavage and caspase-7 activation. Gene expression analysis of MCF-7 cells treated with γ-T3 revealed alterations in the expression of multiple genes involved in cell growth and proliferation, cell death, cell cycle, cellular development, cellular movement and gene expression. Further analysis of differentially modulated genes using Ingenuity Pathway Analysis software suggested modulation of canonical signal transduction or metabolic pathways such as NRF-2-mediated oxidative stress response, TGF-β signaling and endoplasmic reticulum (ER) stress response. Analysis of ER-stress-related proteins in MCF-7 and MDA-MB 231 cells treated with γ-T3 demonstrated activation of PERK and pIRE1α pathway to induce ER stress. Activating transcription factor 3 (ATF3) was identified as the most up-regulated gene (16.8-fold) in response to γ-T3. Activating transcription factor 3 knockdown using siRNA suggested an essential role of ATF3 in γ-T3-induced apoptosis. In summary, we demonstrate that γ-T3 modulates ER stress signaling and have identified ATF3 as a molecular target for γ-T3 in breast cancer cells.
authors.affiliation: Cancer Research Laboratory, Department of Biological and Environmental Sciences, University of the District of Columbia, Washington, DC 20008, USA.
authors.forename: Dorrelyn
authors.initials: D
authors.lastname: Patacsil
authors.forename: Anh Thu
authors.initials: AT
authors.lastname: Tran
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Cho
authors.forename: Simeng
authors.initials: S
authors.lastname: Suy
authors.forename: Francisco
authors.initials: F
authors.lastname: Saenz
authors.forename: Irina
authors.initials: I
authors.lastname: Malyukova
authors.forename: Habtom
authors.initials: H
authors.lastname: Ressom
authors.forename: Sean P
authors.initials: SP
authors.lastname: Collins
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000187:drug effects*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D002839:Chromans; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D014810:Vitamin E; C013649:plastochromanol 8; D011065:Poly(ADP-ribose) Polymerases; D053179:Caspase 7