Antiestrogenic activity of flavonoid phytochemicals mediated via the c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha.
Flavonoid phytochemicals act as both agonists and antagonists of the human estrogen receptors (ERs). While a number of these compounds act by directly binding to the ER, certain phytochemicals, such as the flavonoid compounds chalcone and flavone, elicit antagonistic effects on estrogen signaling independent of direct receptor binding. Here we demonstrate both chalcone and flavone function as cell type-specific selective ER modulators. In MCF-7 breast carcinoma cells chalcone and flavone suppress ERα activity through stimulation of the stress-activated members of the mitogen-activated protein kinase (MAPK) family: c-Jun N-terminal kinase (JNK)1 and JNK2. The use of dominant-negative mutants of JNK1 or JNK2 in stable transfected cells established that the antiestrogenic effects of chalcone and flavone required intact JNK signaling. We further show that constitutive activation of the JNK pathway partially suppresses estrogen (E2)-mediated gene expression in breast, but not endometrial carcinoma cells. Our results demonstrate a role for stress-activated MAPKs in the cell type-specific regulation of ERα function.
Tulane University Medical Center, Department of Medicine, Section of Hematology and Medical Oncology, New Orleans, LA 70112, United States.
Bridgette M
BM
Collins-Burow
James W
JW
Antoon
Daniel E
DE
Frigo
Steven
S
Elliott
Christopher B
CB
Weldon
Stephen M
SM
Boue
Barbara S
BS
Beckman
Tyler J
TJ
Curiel
Jawed
J
Alam
John A
JA
McLachlan
Matthew E
ME
Burow
D045744:Cell Line, Tumor; D002599:Chalcone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047309:Flavones / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*
C506487:ESR1 protein, human; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047309:Flavones; D004958:Estradiol; D002599:Chalcone; D048031:JNK Mitogen-Activated Protein Kinases; C043562:flavone