Melatonin down-regulates HIF-1α expression through inhibition of protein translation in prostate cancer cells

Abstract

Melatonin, the main secretory product of the pineal gland, has been shown to exert an oncostatic activity in cancer cells. Recently, several studies have shown that melatonin has antiangiogenic properties. However, the mechanism by which melatonin exerts antiangiogenenic effects is not understood. Hypoxia inducible factor (HIF)-1 is a transcription factor which mediates adaptive response to changes in tissue oxygenation. HIF-1 is a heterodimer formed by the association of a constitutively expressed HIF-1β subunit and a HIF-1α subunit, the expression of which is highly regulated. In this study, pharmacologic concentrations of melatonin was found to inhibit expression of HIF-1α protein under both normoxic and hypoxic conditions in DU145, PC-3, and LNCaP prostate cancer cells without affecting HIF-1α mRNA levels. Consistent with the reduction in HIF-1α protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of vascular endothelial growth factor. We found that the suppression of HIF-1α expression by melatonin correlated with dephosphorylation of p70S6K and its direct target RPS6, a pathway known to regulate HIF-1α expression at the translational level. Metabolic labeling assays indicated that melatonin inhibits de novo synthesis of HIF-1α protein. Taken together, these results suggest that the pharmacologic concentration of melatonin inhibits HIF-1α expression through the suppression of protein translation in prostate cancer cells.