Estrogen receptor beta (ERbeta) subtype-specific ligands increase transcription, p44/p42 mitogen activated protein kinase (MAPK) activation and growth in human non-small cell lung cancer cells.
In non-small cell lung cancer (NSCLC) cells, 17beta-estradiol increases transcription, activates MAPK, and stimulates proliferation. We hypothesize that estrogen receptor beta (ERbeta) mediates these responses because it, but not ERalpha, is detected in our NSCLC cell lines. To test this, we determined the effects of the ERbeta-selective agonists genistein (GEN) and 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) and the ERalpha-selective agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) in 201T cells. The cells were transfected with either an ERalpha or an ERbeta expression vector and an estrogen response element (ERE)-tk-luciferase reporter construct. PPT increased luciferase activity in cells expressing ERalpha but not ERbeta. GEN and DPN selectively increased luciferase activity in ERbeta-transfected cells at concentrations < or =10 nM. Fulvestrant blocked the GEN- and DPN-mediated increases, indicating that transcription was ER-dependent. GEN but not PPT mediated a significant 1.5-fold increase in reporter activity upon transfection with ERE-tk-luciferase alone, demonstrating that endogenous ERbeta activates transcription. PPT and DPN increased MAPK phosphorylation (2.5-fold and 3.7-fold, respectively). However, only DPN stimulated 201T growth in vitro (p=0.008) and in vivo (p=0.05). We conclude that ERbeta mediates genomic and non-genomic responses to estrogen in 201T cells and that activation of both pathways may be necessary for increased proliferation of these cells.
Hershberger
Pamela A
PA
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. hershbergerpa@upmc.edu
Stabile
Laura P
LP
Kanterewicz
Beatriz
B
Rothstein
Mary E
ME
Gubish
Chris T
CT
Land
Stephanie
S
Shuai
Yongli
Y
Siegfried
Jill M
JM
Nichols
Mark
M
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D036145:Ginsenosides / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012502:Sapogenins / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D011422:Propionates
D047629:Estrogen Receptor beta; D019833:Genistein; D036145:Ginsenosides; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D012502:Sapogenins; D014157:Transcription Factors; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C478359:WDR77 protein, human; C507965:ginsenoside 20S-protopanaxatriol