Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E

Abstract

To examine estrogen-induced growth mechanisms of endometrial carcinoma, we investigated the estrogen-induced activation of the mitogen-activated protein kinase (MAPK) pathway and cell cycle regulators. Estradiol (E 2 ) treatment at concentrations of 10 K8 M and 10 K6 M to estrogen receptor (ER)-positive endometrial carcinoma Ishikawa cells for 24 h resulted in increased cell proliferation by 20% and 28% respectively. The E 2 -induced proliferation was associated with the activation of extracellular signal-regulated kinase (MAPK)3/1 and up-regulation of cyclin D1 and E, which were suppressed by the addition of an MAP2K inhibitor (U0126) or an ER antagonist (ICI 182 780). Then, our screening for estrogen-inducible growth factors identified that IGF1 was up-regulated remarkably by E 2 . Immunoprecipitation using conditioned medium of Ishikawa cells after E 2 treatment confirmed the E 2 -induced secretion of IGF1 protein. Treatment with recombinant IGF1 stimulated cell proliferation in a dose-dependent fashion, in association with MAPK3/1 phosphorylation and up-regulation of cyclin D1 and E. These IGF1-induced responses were suppressed by treatment with MAP2K inhibitor or anti-IGF1 receptor antibody. Immunohistochemical staining confirmed the expression of activated MAPK3/1 in normal proliferative phase endometria and endometrial carcinomas, indicating the involvement of this pathway in actively proliferating endometrial tissues in vivo. These findings suggest that E 2 -induced proliferation of endometrial carcinoma cells is mediated by the MAPK3/1 pathway via autocrine stimulation of IGF1.

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

“…Therefore, the local production and availability of IGF-1 appears to play a role in uterine proliferation. Moreover, evidence also suggests the proliferative effect of E 2 on IGF-1 production in the human epithelium was mediated in an autocrine fashion in human uterine epithelial cells (34). Further evidence came from the use of a growth factor inhibitor in combination with E 2 administration, which partly inhibited the action of estrogen on the uterine weight increase (13).…”

The Impact of Race and Comorbidity on Survival in Endometrial Cancer

“…Whether diabetes is a risk factor for black women is not established as there are currently no studies of risk factors in black women. In endometrial cancer cell lines, estradiol upregulates IGF-1 to increase proliferation in established tumors in vitro (25), likely leading to more aggressive tumors and poorer outcomes; whether these relationships are the same in blacks and whites is not known. We note that there are other differences between blacks and whites in diabetes-related diseases.…”

Knockdown of ICB-1 gene enhanced estrogen responsiveness of ovarian and breast cancer cells

“…The effects of 17-b E 2 on these tissues are either mediated through ER binding to EREs directly regulating gene expression, via ER interaction with other transcription factors or by nonnuclear actions that seem to be mediated by membrane-bound ERs (Rae & Johnson 2005, Kleuser et al 2008, Peng & Jordan 2008. Estrogens are known to stimulate proliferation of hormone-dependent tissues for example by activation of cell cycle genes (Kashima et al 2009).…”