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Signal transduction of receptor‐mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Gα s and Gα q proteins

Signal transduction of receptor‐mediated antiproliferative action of melatonin on human prostate... Abstract: Melatonin has been shown to inhibit the proliferation of malignant and transformed human prostate epithelial cells by transcriptional up‐regulation of p27Kip1 expression via MTNR1A receptor‐mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel. Given that melatonin MTNR1A receptor is a G protein‐coupled receptor, this study was conducted to identify the specific G proteins that mediate the antiproliferative action of melatonin on human prostate epithelial cells. In 22Rv1 and RWPE‐1 cells, knockdown of either Gαs or Gαq, but not Gαi2 expression by RNA interference, abrogated the effects of melatonin on p27Kip1 and cell proliferation. Conversely, cellular overexpression of activated mutants of Gαs and Gαq in 22Rv1 and RWPE‐1 cells mimicked the effects of melatonin on prostate epithelial cell antiproliferation by increasing p27Kip1 expression through downstream activation of PKA and PKC in parallel. Moreover, melatonin or 2‐iodomelatonin induced elevation of adenosine‐3′,5′‐cyclic monophosphate (cAMP) in 22Rv1 and RWPE‐1 cells. The effects of 2‐iodomelatonin on cAMP were blocked by the nonselective MTNR1A/MTNR1B receptor antagonist luzindole but were not affected by the selective MTNR1B receptor antagonist 4‐phenyl‐2‐propionamidotetraline (4‐P‐PDOT). Furthermore, knockdown of Gαs mitigated the stimulatory effects of 2‐iodomelatonin on cAMP. Collectively, the data demonstrated, for the first time, functional coupling of MTNR1A receptor to Gαs in cancerous or transformed human cells expressing endogenous melatonin receptors. Our results also showed that dual activation of Gαs and Gαq proteins is involved in the signal transduction of MTNR1A receptor‐mediated antiproliferative action of melatonin on human prostate epithelial cells. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Pineal Research Wiley

Signal transduction of receptor‐mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Gα s and Gα q proteins

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References (44)

Publisher
Wiley
Copyright
© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S
ISSN
0742-3098
eISSN
1600-079X
DOI
10.1111/j.1600-079X.2010.00795.x
pmid
20695976
Publisher site
See Article on Publisher Site

Abstract

Abstract: Melatonin has been shown to inhibit the proliferation of malignant and transformed human prostate epithelial cells by transcriptional up‐regulation of p27Kip1 expression via MTNR1A receptor‐mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel. Given that melatonin MTNR1A receptor is a G protein‐coupled receptor, this study was conducted to identify the specific G proteins that mediate the antiproliferative action of melatonin on human prostate epithelial cells. In 22Rv1 and RWPE‐1 cells, knockdown of either Gαs or Gαq, but not Gαi2 expression by RNA interference, abrogated the effects of melatonin on p27Kip1 and cell proliferation. Conversely, cellular overexpression of activated mutants of Gαs and Gαq in 22Rv1 and RWPE‐1 cells mimicked the effects of melatonin on prostate epithelial cell antiproliferation by increasing p27Kip1 expression through downstream activation of PKA and PKC in parallel. Moreover, melatonin or 2‐iodomelatonin induced elevation of adenosine‐3′,5′‐cyclic monophosphate (cAMP) in 22Rv1 and RWPE‐1 cells. The effects of 2‐iodomelatonin on cAMP were blocked by the nonselective MTNR1A/MTNR1B receptor antagonist luzindole but were not affected by the selective MTNR1B receptor antagonist 4‐phenyl‐2‐propionamidotetraline (4‐P‐PDOT). Furthermore, knockdown of Gαs mitigated the stimulatory effects of 2‐iodomelatonin on cAMP. Collectively, the data demonstrated, for the first time, functional coupling of MTNR1A receptor to Gαs in cancerous or transformed human cells expressing endogenous melatonin receptors. Our results also showed that dual activation of Gαs and Gαq proteins is involved in the signal transduction of MTNR1A receptor‐mediated antiproliferative action of melatonin on human prostate epithelial cells.

Journal

Journal of Pineal Research – Wiley

Published: Oct 1, 2010

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