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Plos One : Vitamin E Δ-tocotrienol Induces P27Kip1-dependent Cell- Cycle Arrest in Pancreatic Cancer Cells Via an E2F-1- Dependent Mechanism, Volume 7

By El-rifai, Wael

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Book Id: WPLBN0003962335
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Reproduction Date: 2015

Title: Plos One : Vitamin E Δ-tocotrienol Induces P27Kip1-dependent Cell- Cycle Arrest in Pancreatic Cancer Cells Via an E2F-1- Dependent Mechanism, Volume 7  
Author: El-rifai, Wael
Volume: Volume 7
Language: English
Subject: Journals, Science, Medical Science
Collections: Periodicals: Journal and Magazine Collection (Contemporary)
Historic
Publication Date:
Publisher: Plos

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El-Rifai, W. (n.d.). Plos One : Vitamin E Δ-tocotrienol Induces P27Kip1-dependent Cell- Cycle Arrest in Pancreatic Cancer Cells Via an E2F-1- Dependent Mechanism, Volume 7. Retrieved from http://ebook2.worldlibrary.net/


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Description : Vitamin E d-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 d-tocotrienol exerted significant cell growth inhibition pancreatic ductal cancer (PDCA) cells without affecting normal human pancreatic ductal epithelial cell growth. We also showed that d-tocotrienol-induced growth inhibition occurred concomitantly with G1 cell-cycle arrest and increased p27Kip1 nuclear accumulation. This finding is significant considering that loss of nuclear p27Kip1 expression is a well-established adverse prognostic factor in PDCA. Furthermore, d-tocotrienol inactivated RAF-MEK-ERK signaling, a pathway known to suppress p27Kip1 expression. To determine whether p27Kip1 induction is required for d-tocotrienol inhibition of PDCA cell proliferation, we stably silenced the CDKN1B gene, encoding p27Kip1, in MIAPaCa-2 PDCA cells and demonstrated that p27Kip1 silencing suppressed cell-cycle arrest induced by d-tocotrienol. Furthermore, d-tocotrienol induced p27Kip1 mRNA expression but not its protein degradation. p27Kip1 gene promoter activity was induced by dtocotrienol 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 p27Kip1 expression by d-tocotrienol, was confirmed in vivo in a nude mouse xenograft pancreatic cancer model. Our findings reveal a new mechanism, dependent on p27Kip1 induction, by which d-tocotrienol can inhibit proliferation in PDCA cells, providing a new rationale for p27Kip1 as a biomarker for d-tocotrienol efficacy in pancreatic cancer prevention and therapy.


 

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