ArticlePloS one2013
Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- Vitamin intake and pancreatic cancer risk reduction: A meta-analysis of observational studies.Medicine · 2018Pooled it
- Molecular Insights in the Anticancer Activity of Natural Tocotrienols: Targeting Mitochondrial Metabolism and Cellular Redox Homeostasis.Antioxidants (Basel, Switzerland) · 2025Review
- Vitamin E in the management of pancreatic cancer: A scoping review.World journal of gastrointestinal oncology · 2023Article
- What Dietary Patterns and Nutrients are Associated with Pancreatic Cancer? Literature Review.Cancer management and research · 2023Review
- Vitamin E and cancer: an update on the emerging role of γ and δ tocotrienols.European journal of nutrition · 2020Review
- Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols.Molecular carcinogenesis · 2020Review
- Tocotrienols Modulate a Life or Death Decision in Cancers.International journal of molecular sciences · 2019Review
- Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPCancer cell international · 2019Article
- δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.Oncotarget · 2017Article
- Screening of α-Tocopherol Transfer Protein Sensitive Genes in Human Hepatoma Cells (HepG2).International journal of molecular sciences · 2016Article
- A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia.EBioMedicine · 2015Article
- Vitamins in pancreatic cancer: a review of underlying mechanisms and future applications.Advances in nutrition (Bethesda, Md.) · 2015Review
- EGR-1/Bax pathway plays a role in vitamin E δ-tocotrienol-induced apoptosis in pancreatic cancer cells.The Journal of nutritional biochemistry · 2015Article
- Nanoparticle formulation of ormeloxifene for pancreatic cancer.Biomaterials · 2015Article
- Vitamin E δ-tocotrienol prolongs survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic cancer.Cancer prevention research (Philadelphia, Pa.) · 2013Article
- Proto-oncogene activity of melanoma antigen-A11 (MAGE-A11) regulates retinoblastoma-related p107 and E2F1 proteins.The Journal of biological chemistry · 2013Article
- Nuclear p27 expression confers a favorable outcome for nasopharyngeal carcinoma patients.Disease markers · 2013Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
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.
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