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Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells

Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tumor adaptation to microenvironmental hypoxia, and it also exerts important roles in angiogenesis and tumor development. Vanillic acid is a dietary phenolic compound reported to exhibit anticancer properties. However, the mechanisms by whic...

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Autores principales: Gong, Jingli, Zhou, Shengxue, Yang, Shihai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387037/
https://www.ncbi.nlm.nih.gov/pubmed/30678221
http://dx.doi.org/10.3390/ijms20030465
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author Gong, Jingli
Zhou, Shengxue
Yang, Shihai
author_facet Gong, Jingli
Zhou, Shengxue
Yang, Shihai
author_sort Gong, Jingli
collection PubMed
description Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tumor adaptation to microenvironmental hypoxia, and it also exerts important roles in angiogenesis and tumor development. Vanillic acid is a dietary phenolic compound reported to exhibit anticancer properties. However, the mechanisms by which vanillic acid inhibits tumor growth are not fully understood. Here, we investigated the effect of vanillic acid on HIF-1α activation. Vanillic acid significantly inhibits HIF-1α expression induced by hypoxia in various human cancer cell lines. Further analysis revealed that vanillic acid inhibited HIF-1α protein synthesis. Neither the HIF-1α protein degradation rate nor the steady-state HIF-1α mRNA levels were affected by vanillic acid. Moreover, vanillic acid inhibited HIF-1α expression by suppressing mammalian target of rapamycin/p70 ribosomal protein S6 kinase/eukaryotic initiation factor 4E-binding protein-1 and Raf/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways. We found that vanillic acid dose-dependently inhibited VEGF and EPO protein expressions and disrupted tube formation. The results suggest that vanillic acid effectively inhibits angiogenesis. Flow cytometry analysis demonstrated that vanillic acid significantly induced G1 phase arrest and inhibited the proliferation of human colon cancer HCT116 cells. In vivo experiments confirmed that vanillic acid treatment caused significant inhibition of tumor growth in a xenografted tumor model. These studies reveal that vanillic acid is an effective inhibitor of HIF-1α and provides new perspectives into the mechanism of its antitumor activity.
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spelling pubmed-63870372019-02-27 Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells Gong, Jingli Zhou, Shengxue Yang, Shihai Int J Mol Sci Article Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in tumor adaptation to microenvironmental hypoxia, and it also exerts important roles in angiogenesis and tumor development. Vanillic acid is a dietary phenolic compound reported to exhibit anticancer properties. However, the mechanisms by which vanillic acid inhibits tumor growth are not fully understood. Here, we investigated the effect of vanillic acid on HIF-1α activation. Vanillic acid significantly inhibits HIF-1α expression induced by hypoxia in various human cancer cell lines. Further analysis revealed that vanillic acid inhibited HIF-1α protein synthesis. Neither the HIF-1α protein degradation rate nor the steady-state HIF-1α mRNA levels were affected by vanillic acid. Moreover, vanillic acid inhibited HIF-1α expression by suppressing mammalian target of rapamycin/p70 ribosomal protein S6 kinase/eukaryotic initiation factor 4E-binding protein-1 and Raf/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways. We found that vanillic acid dose-dependently inhibited VEGF and EPO protein expressions and disrupted tube formation. The results suggest that vanillic acid effectively inhibits angiogenesis. Flow cytometry analysis demonstrated that vanillic acid significantly induced G1 phase arrest and inhibited the proliferation of human colon cancer HCT116 cells. In vivo experiments confirmed that vanillic acid treatment caused significant inhibition of tumor growth in a xenografted tumor model. These studies reveal that vanillic acid is an effective inhibitor of HIF-1α and provides new perspectives into the mechanism of its antitumor activity. MDPI 2019-01-22 /pmc/articles/PMC6387037/ /pubmed/30678221 http://dx.doi.org/10.3390/ijms20030465 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gong, Jingli
Zhou, Shengxue
Yang, Shihai
Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells
title Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells
title_full Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells
title_fullStr Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells
title_full_unstemmed Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells
title_short Vanillic Acid Suppresses HIF-1α Expression via Inhibition of mTOR/p70S6K/4E-BP1 and Raf/MEK/ERK Pathways in Human Colon Cancer HCT116 Cells
title_sort vanillic acid suppresses hif-1α expression via inhibition of mtor/p70s6k/4e-bp1 and raf/mek/erk pathways in human colon cancer hct116 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387037/
https://www.ncbi.nlm.nih.gov/pubmed/30678221
http://dx.doi.org/10.3390/ijms20030465
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