title: γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer.
abstract: Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.
authors.affiliation: Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. campbese@etsu.edu
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Campbell
authors.forename: Brittney
authors.initials: B
authors.lastname: Rudder
authors.forename: Regenia B
authors.initials: RB
authors.lastname: Phillips
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Whaley
authors.forename: Julie B
authors.initials: JB
authors.lastname: Stimmel
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: Janet
authors.initials: J
authors.lastname: Lightner
authors.forename: Sophie
authors.initials: S
authors.lastname: Dessus-Babus
authors.forename: Michelle
authors.initials: M
authors.lastname: Duffourc
authors.forename: William L
authors.initials: WL
authors.lastname: Stone
authors.forename: David G
authors.initials: DG
authors.lastname: Menter
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: Koyamangalath
authors.initials: K
authors.lastname: Krishnan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D013329:Structure-Activity Relationship; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D053781:Transforming Growth Factor beta2; D014810:Vitamin E; C013649:plastochromanol 8