Mitogenic effects of oestrogen mediated by a non-genomic receptor in human colon.
BACKGROUND
Oestrogens are important mitogens in epithelial cancers, particularly where tumours express complementary receptors. While the traditional model of oestrogen action involves gene-directed (genomic) protein synthesis, it has been established that more rapid, non-genomic steroid hormone actions exist. This study investigated the hypothesis that oestrogen rapidly alters cell membrane activity, intracellular pH and nuclear kinetics in a mitogenic fashion.


METHODS
Crypts isolated from human distal colon and colorectal cancer cell lines were used as robust models. DNA replication and intracellular pH were measured by radiolabelled thymidine incorporation (12 h) and spectrofluorescence imaging respectively. Genomic protein synthesis, sodium-hydrogen exchanger (NHE) and protein kinase C (PKC) activity were inhibited with cycloheximide, ethylisopropylamiloride and chelerythrine chloride respectively.


RESULTS
Oestrogen induced a rapid (less than 5 min) cellular alkalinization of crypts and cancer cells that was sensitive to NHE blockade (P < 0.01) or PKC inhibition (P < 0.01). Oestrogen increased thymidine incorporation by 44 per cent in crypts and by up to 38 per cent in cancer cells (P < 0.01), and this was similarly reduced by inhibiting the NHE (P < 0.01) or PKC (P < 0.05).


CONCLUSIONS
Oestrogen rapidly activates cell membrane and nuclear kinetics by a non-genomic mechanism mediated by PKC but not gene-directed protein synthesis.
Winter
D C
DC
Cork Cancer Research Centre and Department of Surgery, Mercy Hospital and Cellular Physiology Research Unit, University College Cork, Cork, Ireland.
Taylor
C
C
C O'Sullivan
G
G
Harvey
B J
BJ
D002462:Cell Membrane / Q000187:drug effects; D003106:Colon / Q000166:cytology / Q000187:drug effects*; D004261:DNA Replication; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008934:Mitogens / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000502:physiology; D013050:Spectrometry, Fluorescence / Q000379:methods; D014407:Tumor Cells, Cultured
D004967:Estrogens; D008934:Mitogens; D011960:Receptors, Estrogen