Melatonin modulates the expression of VEGF and HIF‐1α induced by CoCl₂ in cultured cancer cells

Abstract

Melatonin is an important natural oncostatic agent. At present there are no data available as to its possible influence on tumor angiogenesis, which is a major biological mechanism responsible for tumor growth and dissemination. It is well known that vascular endothelial growth factor (VEGF) is crucial to a solid tumor's higher vascularization and development. To investigate the possible influence of melatonin on angiogenesis, we studied the effect of melatonin on endogenous VEGF expression in three human cancer cell lines (PANC-1, HeLa and A549 cells). In this study, we report that physiologic concentrations of melatonin have no obvious impact on the VEGF expression, whereas pharmacologic concentrations of melatonin suppress the VEGF mRNA and protein levels induced by hypoxia mimetic cobalt chloride (CoCl(2)). Melatonin also decreases hypoxia-inducible factor (HIF)-1alpha protein levels, suggesting a role for transcription factor HIF-1 in the suppression of VEGF expression. The effect of pharmacologic concentrations of melatonin on VEGF and HIF-1alpha under normoxia is uncertain, which indicates that the regulatory mechanisms of VEGF in the absence or presence of CoCl(2) are different and other or additional transcription factors may be involved. Taken together, our data show that melatonin in high concentrations markedly reduces the expression of endogenous VEGF and HIF-1alpha induced by CoCl(2) in cultured cancer cells.

Effects of melatonin on HIF-1α and VEGF expression and on the invasive properties of hepatocarcinoma cells

“…This is potentially due to the fact that cell normoxia leads to ubiquitination of HIF-1α and subsequent proteasomal degradation (30). Nevertheless, under hypoxic conditions, HIF-1α is stabilized and is able to translocate to the nucleus and induce the expression of multiple genes, including VEGF (30).…”

Effects of oxygen tension and IGF-I on HIF-1α protein expression in mouse blastocysts

“…Negative control embryos were processed as described above, but the primary antibody was omitted. The HeLa cells treated with cobalt chloride (CoCl 2 ; a chemical inducer of HIF-1α) were used as a positive control [20].…”

Melatonin as an Anti-angiogenetic, Immunomodulatory and Antitumoral Agent

“…They stated that physiologic concentrations of melatonin don't have any apparent impact on the VEGF expression, however, pharmacologic concentrations of melatonin suppress the VEGF mRNA and protein degrees brought about by hypoxia echoer cobalt chloride (CoCl2) [5]. Melatonin also decreases HIF-1 alpha protein levels.…”

“…Melatonin also decreases HIF-1 alpha protein levels. Their data display that melatonin in excessive concentration markedly reduces the expression of endogenous VEGF and HIF-1 alpha-induced via CoCl2 in different types of cultured cancers cells [5].…”

“…In order to support the relation between melatonin and VEGF, the study of Dai et al is important [5]. They stated that physiologic concentrations of melatonin don't have any apparent impact on the VEGF expression, however, pharmacologic concentrations of melatonin suppress the VEGF mRNA and protein degrees brought about by hypoxia echoer cobalt chloride (CoCl2) [5].…”