title: Anti-proliferative effects of γ-tocotrienol are associated with suppression of c-Myc expression in mammary tumour cells.
abstract: OBJECTIVE
  Aberrant c-Myc activity plays a central role in cancer transformation. γ-tocotrienol is a member of the vitamin E family that displays potent anti-cancer activity. Here, studies were conducted to determine the role of c-Myc in mediating anti-proliferative effects of γ-tocotrienol in mammary cancer cells.
  
  
  METHODS
  Treatment effects on mouse +SA and human MCF-7 mammary cancer cell proliferation were determined by MTT assay and Ki-67 staining. Protein expression was determined by western blot analysis. Immunofluorescence staining and qRT-PCR were used to characterize cellular c-Myc and MYC levels respectively.
  
  
  RESULTS
  Anti-proliferative effects of γ-tocotrienol were associated with reduction in total c-Myc and phosphorylated-c-Myc-serine 62, and increase in phosphorylated-c-Myc-threonine 58 levels. γ-tocotrienol also reduced PI3K/Akt/mTOR and Ras/MEK/Erk mitogenic signalling, cyclin D1 and cyclin-dependent kinase 4 levels, and increased p27 levels. However, γ-tocotrienol had no effect on MYC mRNA levels. γ-tocotrienol also increased levels of FBW7 (E3 ligase that initiates ubiquitination of c-Myc), but had no effect on serine/threonine phosphatase PP2A or isomerase Pin 1 levels. Combined treatment with GSK3α/β inhibitor LiCl or proteasome inhibitor MG132 blocked γ-tocotrienol-induced reductions in c-Myc.
  
  
  CONCLUSIONS
  These findings indicate that anti-proliferative effects of γ-tocotrienol are associated with reduction in c-Myc that results from increase in GSK-3α/β-dependent ubiquitination and degradation, rather than from reduction in c-Myc synthesis in +SA and MCF-7 mammary cancer cells.
authors.affiliation: School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, 71209, USA.
authors.forename: P
authors.initials: P
authors.lastname: Parajuli
authors.affiliation: School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, 71209, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Tiwari
authors.affiliation: School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, 71209, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Sylvester
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D016271:Proto-Oncogene Proteins c-myc; D014810:Vitamin E; C013649:plastochromanol 8; D024502:alpha-Tocopherol