Transcriptional repression of RORalpha activity in human breast cancer cells by melatonin.
Melatonin has repeatedly been shown to inhibit the proliferation of MCF-7 human breast cancer cells. Previous reports suggest that the actions of melatonin can be mediated either through G-protein coupled membrane receptors or via retinoid orphan receptors (RORalphas). In this study, we demonstrated the expression of RORalpha2, 3, and 4 transcripts in MCF-7 cells. These cells exhibited a high basal level of RORalpha transcriptional activity, which was further stimulated by serum. In the presence of serum, RORalpha transactivation and DNA-binding activity was repressed by melatonin even though melatonin had no effect on RORalpha protein levels. We found that RORalpha transcriptional activity in MCF-7 cells was regulated by modulators of the Ca2+/CaM signaling pathway. Given that melatonin has been reported to modulate the Ca2+/CaM signaling pathway in other tissues, our data indicate that melatonin may affect RORalpha transcriptional activity, expression of RORalpha regulated genes, and even breast cancer cell proliferation via modulation of the Ca2+/CaM signaling pathway.
Dai
J
J
Department of Structural and Cellular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Ram
P T
PT
Yuan
L
L
Spriggs
L L
LL
Hill
S M
SM
D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D020013:Calcium Signaling / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D002147:Calmodulin; D004268:DNA-Binding Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D020033:Protein Isoforms; D012333:RNA, Messenger; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008550:Melatonin