Details

Autor(en) / Beteiligte

• Hodul, Pamela J
• Dong, Yanbin
• Husain, Kazim
• Pimiento, Jose M
• Chen, Jiandong
• Zhang, Anying
• Francois, Rony
• Pledger, Warren J
• Coppola, Domenico
• Sebti, Said M
• Chen, Dung-Tsa
• Malafa, Mokenge P

Titel

Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism

Ist Teil von

• PloS one, 2013, Vol.8 (2), p.e52526

Ort / Verlag

United States: Public Library of Science (PLoS)

Erscheinungsjahr

2013

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.