17beta-Estradiol (E2) is well known to interact with intracellular receptors that act as nuclear
transcription factors. However, abundant evidence now indicates that E2 can also rapidly induce several nongenomic effects through signaling pathways related to cell growth, preservation, and differentiation. We studied the nongenomic effects of E2 in two human
endometrial carcinoma cell lines, Ishikawa (
estrogen receptor (ER) positive) and Hec-1A (ER negative or low) by cultivating them with either E2 or its membrane-impermeable conjugate,
E2-BSA. We found that phosphorylation of Erk1/2 could be induced by either E2 or
E2-BSA in Ishikawa cells. In Hec-1A cells, only E2 was able to induce Erk1/2 phosphorylation. Although the existence of a nongenomic component to the response was indicated by the finding that it could not be completely inhibited by the ER antagonist
ICI182780,and it can also be inhibited by
calcium inhibitor
Nifedipine partly. Phosphorylation of Akt could not be induced, either by E2 or
E2-BSA, in either cell line. Both E2 and
E2-BSA elicited
calcium influx in Ishikawa cells. In contrast to these nongenomic effects, only E2 was able to stimulate expression of the
anti-apoptotic-protein Bcl-2. Taken together, these data indicate that nongenomic effects such as Erk1/2 phosphorylation and
calcium influx can be initiated from the membrane in Ishikawa cell, and
calcium can activate Erk1/2 phosphorylation. Except for ER, there must be other binding location of
estrogen in
endometrial cancer cells, and the nongenomic effects of
estrogen initiated from plasma membrane by
E2-BSA cannot lead to transcriptional effect of Bcl-2 expression.