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-1 beta subunit and a HIF-1 alpha subunit, the expression of which is highly regulated. In this study, pharmacologic concentrations of melatonin was found to inhibit expression of HIF-1 alpha protein under both normoxic and hypoxic conditions in DU145, PC-3, and LNCaP prostate cancer cells without affecting HIF-1 alpha mRNA levels. Consistent with the reduction in HIF-1 alpha protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of vascular endothelial growth factor. We found that the suppression of HIF-1 alpha expression by melatonin correlated with dephosphorylation of p70S6K and its direct target RPS6, a pathway known to regulate HIF-1 alpha expression at the translational level. Metabolic labeling assays indicated that melatonin inhibits de novo synthesis of HIF-1 alpha protein. Taken together, these results suggest that the pharmacologic concentration of melatonin inhibits HIF-1 alpha expression through the suppression of protein translation in prostate cancer cells.

Basic Mechanisms Involved in the Anti-Cancer Effects of Melatonin

“…A more recent study [184] carried out on different prostate cancer cell lines (DU145, PC-3, and LNCaP) confirmed that pharmacologic concentrations of melatonin inhibit the expression of HIF-1 protein under both normoxic and hypoxic conditions. Consistent with the reduction in HIF-1 protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of VEGF [184]. These data make research on the angiogenic properties of melatonin of significant importance with possible future clinical applications in the field of oncology therapies.…”

“…In three different human cancer cell lines studied (PANC-1, HeLa and A549 cells), pharmacologic concentrations of melatonin suppressed VEGF mRNA and protein levels induced by hypoxia, and also decreases HIF-1 protein, suggesting a role for transcription factor HIF-1 in the suppression of VEGF expression [181]. A more recent study [184] carried out on different prostate cancer cell lines (DU145, PC-3, and LNCaP) confirmed that pharmacologic concentrations of melatonin inhibit the expression of HIF-1 protein under both normoxic and hypoxic conditions. Consistent with the reduction in HIF-1 protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of VEGF [184].…”

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

“…In vitro studies have reported that melatonin is able to inhibit the expression of HIF-1α in prostate cancer cells (21) and glioblastoma (22), as well as VEGF expression in breast (23) and pancreatic cancer cells (5), as well as glioblastoma (22). Carbajo-Pescador et al (24) reported that melatonin exerted antiangiogenic activity in HepG2 cells by interfering with the transcriptional activation of the VEGF gene by HIF-1α and signal transducer and activator of transcription 3.…”

LNCaP Prostate Cancer Growth In Vivo: Oncostatic Effects of Melatonin as Compared to Hypoxia and Reoxygenation

“…A breakthrough in understanding the mechanisms underlying the oncostatic properties of melatonin came along with unraveling the relationship between melatonin and the hypoxia signaling path. Melatonin indeed inhibits HIF-1 protein expression in normoxic and hypoxic DU145, PC-3 and LNCaP prostate cancer cells without affecting HIF-1 mRNA levels (Park et al, 2009). In HCT116 human colon cancer cells, melatonin destabilizes HIF-1, suppresses its transcriptional activity, thereby decreasing VEGF expression (Park et al, 2010).…”

“…These observations suggest an important role for hypoxia dependent pathways that do not involve HIF-1, and for the pharmacological treatments able to modulate these pathways. Pharmacologic concentrations of melatonin inhibit in vitro expression of HIF-1 protein under both normoxic and hypoxic conditions in DU145, PC-3, and LNCaP prostate cancer cells (Park et al, 2009). This effect, perhaps a result of the antioxidant activity of melatonin against ROS induced by hypoxia, and the subsequent suppression of HIF-1 transcriptional activity decreases VEGF expression in HCT116 human colon cancer cell line (Park et al, 2010).…”