Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1α

Akira Shibata, Kiyotaka Nakagawa, Phumon Sookwong, Tsuyoshi Tsuduki, Shuhei Tomita, Hitoshi Shirakawa, Michio Komai, Teruo Miyazawa

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66 Citations (Scopus)

Abstract

Tocotrienol (T3), unsaturated vitamin E, has recently gained considerable attention as a potent antiangiogenic agent minimizing tumor growth, the exact intracellular mechanisms of which remain poorly understood. Because hypoxia-inducible factor-1α (HIF-1α), its downstream target vascular endothelial growth factor (VEGF), and other angiogenic factors such as interleukin-8 (IL-8) and cyclooxygenase 2 (COX-2) play critical roles in neovascularization, we tested the hypothesis that the inhibitory effect of T3 on tumor angiogenesis is via regulation of these angiogenic factors. We used 2 cancer cell lines, human colorectal adenocarcinoma cells (DLD-1) and human hepatoma cells (HepG2). T3 isomers (2 μmol/L) inhibited hypoxia-induced VEGF secretion from DLD-1, with δ-T3 showing potent inhibition. δ-T3 suppressed hypoxia-induced VEGF and IL-8 expression in DLD-1 at both mRNA and protein levels, and we found the inhibitory mechanism of δ-T3 by reducing HIF-1α protein expression or increasing HIF-1α degradation. Also, δ-T3 (2 μmol/L) did not affect hypoxia-induced COX-2 mRNA expression; however, δ-T3 tended to suppress (P = 0.044) hypoxia-induced COX-2 protein expression, implying a possible post-transcriptional mechanism by δ-T3. Overall, our results confirmed that T3 has an inhibitory effect on angiogenic factor secretion from cancer cells and revealed the possible mechanisms, providing new information about the antiangiogenic effects of T3.

Original languageEnglish
Pages (from-to)2136-2142
Number of pages7
JournalJournal of Nutrition
Volume138
Issue number11
DOIs
Publication statusPublished - 2008 Nov

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics

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