Pancreatic Beta-Cell Proliferation Induced by Estradiol-17β is Foxo1 Dependent

Abstract

Estradiol-17β (E2) and the Foxo1 transcription factor have each been implicated in the regulation of β-cell proliferation. Interaction between Foxo1and estrogen receptor alpha (ERα), effecting cell cycle, has been demonstrated in breast cancer cells, but has not been studied thus far in β-cells. Using human islets and the INS1-E β-cell line, this study investigated the contribution of Foxo1 to E2-mediated β-cell replication. Foxo1 expression was knocked down in INS1-E cells using siRNA and Foxo1 activity was inhibited in human islets with a specific Foxo1 inhibitor (AS1842856). Cells were treated with E2 and the ERα agonist PPT and evaluated for proliferation by [H]-thymidine incorporation and for transcriptional activity through the estrogen response element by the luciferase assay. As Foxo1 activity is regulated by post-translational modifications, the effect of E2 on phosphorylation was also assessed. In INS1-E cells, knock down of Foxo1 abrogated the proliferative response to E2 and PPT. In human islets, inhibition of Foxo1 abrogated E2-mediated proliferation and attenuated the response to PPT. Foxo1 knock down and inhibition reduced activity through the estrogen response element by 25% (p<0.05) and 50% (p<0.01) respectively, in INS1-E cells. E2 increased Foxo1 phosphorylation in a time dependent manner in INS1-E and human islets (p<0.01, p<0.05, respectively). These findings suggest that Foxo1 is involved in E2-mediated proliferation in INS1-E cells and human islets. This may have implications vis-à-vis variations in circulating endogenous E2 concentrations in diabetes.

Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1

“…FoxO1 is a downstream effector of insulin/insulin-like growth factor-I signaling and can be regulated by Akt via phosphorylation, following nuclear exclusion (13,24). Furthermore, FoxO1 is a key regulatory factor governing a variety of physiological functions, including the pancreatic β-cells proliferation, apoptosis and autophagy (14,15,18,37). FoxO1 also protects pancreatic β-cells by inhibiting thioredoxin-interacting protein transcription (38).…”

Cross-talk between the ER pathway and the lncRNA MAFG-AS1/miR-339-5p/ CDK2 axis promotes progression of ER+ breast cancer and confers tamoxifen resistance

“…Thus, MAFG-AS1 and ERα may form a positive feedback loop, implying that they can promote each other to a high level of expression in ER+ breast cancer. It has been reported that FOXO1 can act as a transcription factor for ERα in breast cancer [ 40 , 41 ], which may contribute to positive feedback formation. This may also explain the mechanism of tamoxifen resistance induced by cross-talk between the cell cycle and ER signaling pathway.…”

Spatiotemporal expression and regulation of FoxO1 in mouse uterus during peri-implantation period

“…We agree with the findings of Vasquez et al indicating that FoxO1 expression is regulated by progesterone [31], moreover we found that estrogen is also another regulator of FoxO1 expression during implantation. A recent study also found that pancreatic beta-cell proliferation induced by estradiol-17beta is FoxO1 dependent and the authors propose a model of E2/ER-Foxo1 interactions effecting DNA synthesis, in beta-cells [41] Since few studies investigated the molecular mechanism regarding regulation of FoxO1 expression by estrogen so far, then topic needs further evaluation especially during embryo implantation and also in reproduction.…”