Ascorbic acid and ascorbate-2-phosphate decrease HIF activity and malignant properties of human melanoma cells

Hypoxia inducible factor-1 alpha (HIF-1α) is thought to play a role in melanoma carcinogenesis. Posttranslational regulation of HIF-1α is dependent on Prolyl hydroxylase (PHD 1-3) and Factor Inhibiting HIF (FIH) hydroxylase enzymes, which require ascorbic acid as a co-factor for optimal function. De...

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Bibliographic Details
Published in:BMC cancer 2015-11, Vol.15 (865), p.867, Article 867
Main Authors: Miles, Sarah L, Fischer, Adam P, Joshi, Sandeep J, Niles, Richard M
Format: Article
Language:English
Subjects:
Acids
Ascorbic Acid - analogs & derivatives
Ascorbic Acid - pharmacology
Care and treatment
Cell Hypoxia
Cell Line, Tumor
Complications and side effects
Enzymes
Gene Expression
Gene Expression Regulation, Neoplastic - drug effects
Genes, Reporter
Health aspects
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Melanoma
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Metastasis
Neoplasm Metastasis
Physiology
Protein Stability - drug effects
Proteins
Risk factors
Skin cancer
Transcription factors
Transcription, Genetic - drug effects
Tumors
Vitamin C
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Summary:Hypoxia inducible factor-1 alpha (HIF-1α) is thought to play a role in melanoma carcinogenesis. Posttranslational regulation of HIF-1α is dependent on Prolyl hydroxylase (PHD 1-3) and Factor Inhibiting HIF (FIH) hydroxylase enzymes, which require ascorbic acid as a co-factor for optimal function. Depleted intra-tumoral ascorbic acid may thus play a role in the loss of HIF-1α regulation in melanoma. These studies assess the ability of ascorbic acid to reduce HIF-1α protein and transcriptional activity in metastatic melanoma and reduce its invasive potential. HIF-1α protein was evaluated by western blot, while transcriptional activity was measured by HIF-1 HRE-luciferase reporter gene activity. Melanoma cells were treated with ascorbic acid (AA) and ascorbate 2-phosphate (A2P) to assess their ability to reduce HIF-1α accumulation and activity. siRNA was used to deplete cellular PHD2 in order to evaluate this effect on AA's ability to lower HIF-1α levels. A2P's effect on invasive activity was measured by the Matrigel invasion assay. Data was analyzed by One-way ANOVA with Tukey's multiple comparisons test, or Student-T test as appropriate, with p
ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-015-1878-5