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Abstract
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.
Highlights
Hypoxia is a common phenomenon in the majority of human tumors and known to be involved in metastasis [1,2]
Hypoxia-inducible factor 1α (HIF-1α) expression is induced by several growth factors and their cognate receptors that signal through PI3K or Ras/MAPK pathways [6,7,8]
The results showed that the vanillic acid or rapamycin suppressed the expression of HIF-1α, which was further inhibited by the combination of vanillic acid and rapamycin (Figure 4C,G)
Summary
Hypoxia is a common phenomenon in the majority of human tumors and known to be involved in metastasis [1,2]. Tumor cells promote angiogenic activity through increases in hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin (EPO), cyclin D1 protein expression, which are essential for tumor growth. Hypoxia-inducible factor 1α (HIF-1α) is a heterodimeric transcription factor composed of two subunits, O2-regulated HIF-1α and constitutively expressed HIF-1β subunits [3]. The HIF-1α protein is targeted for degradation by a PHD that uses ascorbic acid, iron, and oxygen as cofactors to hydroxylate proline residues (pro-564 and pro-402) in the presence of 2-alphaketoglutarate. Asparagine 803 in the transactivated structure domain inhibits hydroxylation of HIF-1 in fully oxygenated cells and blocks the binding of coactivators p300 and CBP. Hypoxia-inducible factor 1α (HIF-1α) expression is induced by several growth factors and their cognate receptors that signal through PI3K or Ras/MAPK pathways [6,7,8]
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