Abstract
Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR). It was also found that vanillin significantly suppresses HIF-1α mRNA expression and de novo HIF-1α protein synthesis. To understand the suppressive mechanism of vanillin on HIF-1α expression, chromatin immunoprecipitation was performed. Consequently, it was found that vanillin causes inhibition of promoter occupancy by signal transducer and activator of transcription 3 (STAT3), but not nuclear factor-κB (NF-κB), on HIF1A. Furthermore, an in vitro migration assay revealed that the motility of melanoma cells stimulated by hypoxia was attenuated by vanillin treatment. In conclusion, we demonstrate that vanillin might be a potential anti-metastatic agent that suppresses metastatic gene expression and migration activity under hypoxia via the STAT3-HIF-1α signaling pathway.
Highlights
Malignant melanoma is a skin cancer that develops from the abnormal growth and differentiation of melanocytes with hyperpigmentation; the incidence of melanoma cases has been increasing, and this particular skin cancer is associated with a high rate of mortality caused by early and rapid metastasis [1]
For this degradation to occur, hypoxia-inducible factor-1α (HIF-1α) is hydroxylated by the prolyl 4-hydroxylase (P4H) enzyme into proline 402 and 564 residues, which cause hypoxia-inducible factor (HIF)-1α to bind to the von Hippel-Lindau protein (VHL) E3-ubiquitin ligase complex, leading to ubiquitination of this complex and subsequent signaling for proteasomal degradation
Taking into consideration all of the above facts, this study focused on the role of vanillin in the suppression of cancer cell motility and the mechanism of HIF-1α inhibition under hypoxic environments in A2058 and A375 malignant melanoma cells
Summary
Malignant melanoma is a skin cancer that develops from the abnormal growth and differentiation of melanocytes with hyperpigmentation; the incidence of melanoma cases has been increasing, and this particular skin cancer is associated with a high rate of mortality caused by early and rapid metastasis [1]. Given the fact that a hypoxic microenvironment is a major feature in multiple types of solid cancers including melanoma, hypoxia-inducible factor-1 (HIF-1) composed of α and β subunits is a pivotal transcription factor in the adaptation of cells to low oxygen conditions. HIF-1α gets degraded before it can be translocated to the nucleus, associate with HIF-1β, and begin the hypoxic response that is conducive to tumor formation. For this degradation to occur, HIF-1α is hydroxylated by the prolyl 4-hydroxylase (P4H) enzyme into proline 402 and 564 residues, which cause HIF-1α to bind to the von Hippel-Lindau protein (VHL) E3-ubiquitin ligase complex, leading to ubiquitination of this complex and subsequent signaling for proteasomal degradation. HIF-1α in hypoxic microenvironments transcriptionally increases various transcripts related to stimulation of cell migration and invasion, including fibronectin 1 (FN1), urokinase plasminogen activator receptor (uPAR), lysyl oxidase-like 2 (LOXL2), and matrix metalloproteinases (MMPs) [8]
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