Capsaicin regulates vascular endothelial cell growth factor expression by modulation of hypoxia inducing factor-1alpha in human malignant melanoma cells.
OBJECTIVE
Capsaicin (8-Methyl-N-Vanillyl-6-nonenamide), a known natural dietary chemopreventive agent, inhibits malignant melanoma cell proliferation. In the present study, we examined the effect of capsaicin on constitutive and induced vascular endothelial cell growth factor (VEGF) expression in malignant melanoma cells.


RESULTS
Capsaicin treatment resulted in enhanced VEGF protein secretion in malignant melanoma cells independent of IL-1beta and TNF-alpha. The observed up-regulation of VEGF production by capsaicin was concentration- and duration-dependent and was inversely associated with inhibition of melanoma cell proliferation. We observed an increase in hypoxia-inducible factor (HIF)-1alpha and VEGF mRNA expression in capsaicin-treated melanoma cells. Further, an electrophoretic mobility shift assay (EMSA) from nuclear extracts from melanoma cells showed a decrease in constitutive activation of NF-kappaB and enhanced HIF-1alpha binding activity to hypoxia response element (HRE) in melanoma cells treated with different concentrations of capsaicin.


CONCLUSIONS
These data suggest that inhibition of cellular proliferation by capsaicin follows enhanced VEGF production by remaining melanoma cells by enhancing HIF-1alpha expression and binding to HRE.
Patel
Prabhudas S
PS
Department of Pathology and Microbiology, University of Nebraska Medical Center, 987660 Nebraska Medical Center, Omaha, NE 68123, USA.
Yang
Shillin
S
Li
Aihua
A
Varney
Michelle L
ML
Singh
Rakesh K
RK
D002211:Capsaicin / Q000494:pharmacology*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016328:NF-kappa B; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D002211:Capsaicin