Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-alpha-mediated transcription in MCF-7 breast cancer cells.
The aim of this study was to determine whether the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway is involved in genistein- and equol-induced cell proliferation and estrogen receptor (ER) alpha transactivation. For MCF-7 human breast cells, low concentrations of genistein and equol enhanced proliferation and induced MCF-7 cells to enter the S-phase. Genistein- and equol-induced cell proliferation and S-phase entry were blocked by the ERalpha antagonists 4-hydroxytamoxifen and ICI 182,780 and by the mitogen-activated protein kinase 1/2 inhibitor U0126. These data indicated that ERalpha and mitogen-activated protein extracellular kinase/ERK signaling were required for the effects of genistein/equol on cell growth and cell cycle progression. Genistein and equol induced delayed and prolonged activation of ERK1/2. Inhibition of ERK1/2 phosphorylation by U0126 led to complete suppression of genistein- and equol-induced estrogen response element reporter activity and to suppression of the estrogen-responsive gene pS2. The anti-estrogen ICI had no effect on genistein- and equol-induced ERK1/2 phosphorylation. These results suggest that activation of ERK1/2 lies upstream of ER-mediated transcription, and that ERK1/2 activation is necessary for the transactivation of ERalpha. In conclusion, genistein and equol elicit a delayed activation of ERK1/2, and this activation appears to be involved in the proliferation of breast cancer cells and estrogen-dependent transcriptional activation.
The Key Laboratory of Reproductive Medicine of Jiangsu Province, Institute of Toxicology, Nanjing Medical University, Jiangsu, Nanjing, China.
Huaqing
H
Liu
Juan
J
Du
Chunyan
C
Hu
Hong
H
Qi
Xinru
X
Wang
Shoulin
S
Wang
Qizhan
Q
Liu
Zhong
Z
Li
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D060754:Equol; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D048789:Phytoestrogens / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects*
C007610:4',7-dihydroxy-3,4-dihydroisoflavone; D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D007529:Isoflavones; D048789:Phytoestrogens; D060754:Equol; D019833:Genistein; D048049:Extracellular Signal-Regulated MAP Kinases