title: Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism.
abstract: Vitamin E δ-tocotrienol has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we demonstrated that δ-tocotrienol exerted significant cell growth inhibition pancreatic ductal cancer (PDCA) cells without affecting normal human pancreatic ductal epithelial cell growth. We also showed that δ-tocotrienol-induced growth inhibition occurred concomitantly with G(1) cell-cycle arrest and increased p27(Kip1) nuclear accumulation. This finding is significant considering that loss of nuclear p27(Kip1) expression is a well-established adverse prognostic factor in PDCA. Furthermore, δ-tocotrienol inactivated RAF-MEK-ERK signaling, a pathway known to suppress p27(Kip1) expression. To determine whether p27(Kip1) induction is required for δ-tocotrienol inhibition of PDCA cell proliferation, we stably silenced the CDKN1B gene, encoding p27(Kip1), in MIAPaCa-2 PDCA cells and demonstrated that p27(Kip1) silencing suppressed cell-cycle arrest induced by δ-tocotrienol. Furthermore, δ-tocotrienol induced p27(Kip1) mRNA expression but not its protein degradation. p27(Kip1) gene promoter activity was induced by δ-tocotrienol through the promoter's E2F-1 binding site, and this activity was attenuated by E2F-1 depletion using E2F-1 small interfering RNA. Finally, decreased proliferation, mediated by Ki67 and p27(Kip1) expression by δ-tocotrienol, was confirmed in vivo in a nude mouse xenograft pancreatic cancer model. Our findings reveal a new mechanism, dependent on p27(Kip1) induction, by which δ-tocotrienol can inhibit proliferation in PDCA cells, providing a new rationale for p27(Kip1) as a biomarker for δ-tocotrienol efficacy in pancreatic cancer prevention and therapy.
authors: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors: Pamela J
authors: PJ
authors: Hodul
authors: Yanbin
authors: Y
authors: Dong
authors: Kazim
authors: K
authors: Husain
authors: Jose M
authors: JM
authors: Pimiento
authors: Jiandong
authors: J
authors: Chen
authors: Anying
authors: A
authors: Zhang
authors: Rony
authors: R
authors: Francois
authors: Warren J
authors: WJ
authors: Pledger
authors: Domenico
authors: D
authors: Coppola
authors: Said M
authors: SM
authors: Sebti
authors: Dung-Tsa
authors: DT
authors: Chen
authors: Mokenge P
authors: MP
authors: Malafa
mesh_terms: D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D014810:Vitamin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; C082097:tocotrienol, delta
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