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

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Melatonin, a pineal gland hormone, exhibits oncostatic and antiangiogenic properties in cancer.
• The precise mechanism of melatonin's antiangiogenic effects remains unclear.
• Hypoxia-inducible factor-1 (HIF-1) is crucial for cellular adaptation to hypoxia and promotes tumor growth.

Purpose of the Study:

• To investigate the mechanism by which melatonin exerts antiangiogenic effects in prostate cancer cells.
• To determine the effect of melatonin on Hypoxia-inducible factor-1 alpha (HIF-1α) expression and activity.
• To elucidate the role of protein translation regulation in melatonin's action.

Main Methods:

• Pharmacologic concentrations of melatonin were applied to DU145, PC-3, and LNCaP prostate cancer cells under normoxic and hypoxic conditions.
• HIF-1α protein and mRNA levels, HIF-1 transcriptional activity, and vascular endothelial growth factor release were assessed.
• p70S6K and RPS6 phosphorylation status and de novo protein synthesis were analyzed using metabolic labeling assays.

Main Results:

• Melatonin significantly inhibited HIF-1α protein expression without altering HIF-1α mRNA levels in prostate cancer cells.
• Melatonin suppressed HIF-1 transcriptional activity and reduced vascular endothelial growth factor release.
• The observed suppression of HIF-1α was linked to the dephosphorylation of p70S6K and RPS6, indicating translational regulation.
• Metabolic labeling confirmed that melatonin inhibits the de novo synthesis of HIF-1α protein.

Conclusions:

• Pharmacologic concentrations of melatonin inhibit HIF-1α protein expression in prostate cancer cells primarily by suppressing protein translation.
• This mechanism contributes to melatonin's antiangiogenic effects and potential oncostatic activity.
• Targeting protein translation pathways offers a novel strategy for cancer therapy using melatonin.