Abstract
Human endometrium decidualization, a differentiation process involving biochemical and morphological changes, is a prerequisite for embryo implantation and successful pregnancy. Here, we show that the mammalian target of rapamycin (mTOR) is a crucial regulator of 8-bromoadenosine 3’,5’-cyclic monophosphate (8-Br-cAMP)-induced decidualization in human endometrial stromal cells. The level of mSin1 in mTOR complex 2 (mTORC2) and DEPTOR in mTOR complex 1 (mTORC1) decreases during 8-Br-cAMP-induced decidualization, resulting in decreased mTORC2 activity and increased mTORC1 activity. Notably, DEPTOR displacement increases the association between raptor and insulin receptor substrate-1 (IRS-1), facilitating IRS-1 phosphorylation at serine 636/639. Finally, both S473 and T308 phosphorylation of Akt are reduced during decidualization, followed by a decrease in forkhead box O1 (FOXO1) phosphorylation and an increase in the mRNA levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1). Taken together, our findings reveal a critical role for mTOR in decidualization, involving the differential regulation of mTORC1 and mTORC2.
Highlights
Decidualization is the differentiation process of endometrial stromal (ES) cells, which determines the successful implantation of an embryo and the subsequent formation of a functional placenta[1]
To gain insight into the involvement of mammalian target of rapamycin (mTOR) signaling in successful embryo implantation and pregnancy, we assessed mTOR signaling during in vitro decidualization, a process that is closely related to stromal differentiation in vivo[1]
We show that both mTOR complex 1 (mTORC1) activation and mTOR complex 2 (mTORC2) inactivation are involved in 8-Br-cAMPinduced decidualization
Summary
Decidualization is the differentiation process of endometrial stromal (ES) cells, which determines the successful implantation of an embryo and the subsequent formation of a functional placenta[1]. This process involves the morphological transformation of fibroblast-like ES cells to enlarged decidual cells, which are biochemically and functionally distinct cells. It has been reported that mTOR is a critical regulator of diverse differentiation processes, such as myogenesis[8,9], adipogenesis[10,11], T-cell differentiation[12], and hepatic differentiation[13], suggesting that it may be involved in decidualization. There is evidence for the functional involvement of mTOR signaling during pregnancy. mTOR-
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