Mitogenic effects of oestrogen mediated by a non-genomic receptor in humancolon

Background: Oestrogens are important mitogens in epithelial cancers, partic ularly where tumours express complementary receptors. While the traditional model of oestrogen action involves gene-directed (genomic) protein synthes is, it has been established that more rapid, non-genomic steroid hormone ac tions exist. This study investigated the hypothesis that oestrogen rapidly alters cell membrane activity, intracellular pH and nuclear kinetics in a m itogenic fashion. Methods: Crypts isolated from human distal colon and colorectal cancer cell lines were used as robust models. DNA replication and intracellular pH wer e measured by radiolabelled thymidine incorporation (12 h) and spectrofluor escence imaging respectively. Genomic protein synthesis, sodium-hydrogen ex changer (NHE) and protein kinase C (PKC) activity were inhibited with cyclo heximide, ethylisopropylamiloride and chelerythrine chloride respectively. Results: Oestrogen induced a rapid (less than 5 min) cellular alkalinizatio n of crypts and cancer cells that was sensitive to NHE blockade (P < 0.01) or PKC inhibition (P < 0.01). Oestrogen increased thymidine incorporation b y 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). Conclusion: Oestrogen rapidly activates cell membrane and nuclear kinetics by a non-genomic mechanism mediated by PKC but not gene-directed protein sy nthesis.