Melatonin, an Endogenous-specific Inhibitor of Estrogen Receptor α via Calmodulin
Journal of Biological Chemistry
Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E 2 ) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E 2 -induced ER␣-mediated transcription in both estrogen response element-and AP1-containing promoters, whereas ER␤-mediated transactivation is not inhibited or even
... nhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ER␣/ER␤ ratio, and ectopic expression of ER␤ results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ER␣-calmodulin (CaM) complex, thus impairing the binding of E 2 ⅐ER␣⅐CaM complex to DNA and, therefore, preventing ER␣-dependent transcription. Moreover the mutant ER␣ (K302G,K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ER␣-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ER␣, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ER␣ at different levels, representing two independent ways to control ER␣ activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.