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The Gα i and Gα q proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation
Author(s) -
Lai Ling,
Yuan Lin,
Chen Qi,
Dong Chunmin,
Mao Lulu,
Rowan Brian,
Frasch Tripp,
Hill Steven M.
Publication year - 2008
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2008.00620.x
Subject(s) - melatonin , endocrinology , thyroid , thyroid hormone receptor , medicine , breast cancer , hormone , melatonin receptor , cell growth , steroid , receptor , steroid hormone , biology , cancer research , cancer , biochemistry
Melatonin, via its MT1 receptor, but not the MT2 receptor, can modulate the transcriptional activity of various nuclear receptors – estrogen receptor alpha (ERα) and retinoic acid receptor alpha (RARα), but not ERβ– in MCF‐7, T47D, and ZR‐75‐1 human breast cancer cell lines. The anti‐proliferative and nuclear receptor modulatory actions of melatonin are mediated via the MT1 G protein‐coupled receptor expressed in human breast cancer cells. However, the specific G proteins and associated pathways involved in the nuclear receptor transcriptional regulation by melatonin are not yet clear. Upon activation, the MT1 receptor specifically couples to the G αi2 , G αi3 , G αq , and G αll proteins, and via activation of G αi2 proteins, melatonin suppresses forskolin‐induced 3′,5′‐cyclic adenosine monophosphate production, while melatonin activation of G αq , is able to inhibit phospholipid hydrolysis and ATP’s induction of inositol triphosphate production in MCF‐7 breast cancer cells. Employing dominant‐negative and dominant‐positive) forms of these G proteins, we demonstrate that G αi2 proteins mediate the suppression of estrogen‐induced ERα transcriptional activity by melatonin, while the G q protein mediates the enhancement of retinoid‐induced RARα transcriptional activity by melatonin. However, the growth‐inhibitory actions of melatonin are mediated via both G αi2 and G αq proteins.