The Role of mTOR and eIF Signaling in Benign Endometrial Diseases

Abstract

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.

Keywords: adenomyosis; eIFs; endometriosis; endometritis; mTOR signaling; typical endometrial hyperplasia.

Figure 1

Cross-talk between estrogen and PI3K/AKT/mTOR signaling pathway (1) ERs induce the expression of upstream regulators of the PI3K/AKT/mTOR pathway. (2) Activated ER directly binds to PI3K and promotes its phosphorylation. (3) Estrogen-bound ER attaches to Raptor, causing its translocation to the nucleus. (4) mTORC1 leads to ER phosphorylation and activation via S6K1. (5) Low PTEN expression and thus aberrant PI3K/AKT/mTOR pathway activation may lead to progesterone resistance in the endometrium. E2, estradiol; PG, progesterone; ER, estrogen receptor; PGR, progesterone receptor; GF, growth factor; RTK, receptor tyrosine kinase; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homolog; AKT, protein kinase B; Raptor, regulatory-associated protein of mTOR; mTORC1, mammalian target of rapamycin complex 1; S6K1, p70S6 Kinase 1, eIF4E, eukaryotic translation initiation factor 4E. Graphic created with BioRender.com.

Figure 2

mTOR signaling in PCOS-induced endometrial hyperplasia Glucose metabolism in the uterus is of essential importance for normal endometrial function. Hyperinsulinemia and insulin resistance are major disorders involved in the pathogenesis of PCOS and are believed to contribute to the development of EH in women with this condition. (1) Normally, S6K1 phosphorylates IRS1, thereby preventing the association of IRS1 with the insulin receptor. This negative feedback mechanism desensitizes and protects the cell from further insulin stimulation. When mTORC1 is chronically activated, for example, due to excessive glucose consumption, the sustained downstream stimulation of S6K1 increases IRS1 phosphorylation. This decreases its responsiveness to insulin, thus rendering the cell insulin resistant [109]. (2) mTORC2 influences insulin sensitivity by impairing IRS1 and AKT function. (3) GLUT-4 expression and translocation to the plasma membrane are enhanced by AMPK and AKT, respectively [109,117]. (4) High androgen levels in PCOS restrain apoptosis and increase the proliferative potential of endometrial cells by stimulating mTOR signaling via AMPK inactivation. (5) Metformin restrains EH by suppressing the mTOR pathway through AMPK stimulation. It has also been shown that metformin increases GLUT-4 and decreases AR levels in the endometrium, probably via the mTOR pathway [118]. IGF, insulin-like growth factor; IRS1, insulin receptor substrate 1; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; mTORC2, mammalian target of rapamycin complex 2; mTORC1, mammalian target of rapamycin complex 1; S6K1, p70S6 kinase 1; AMPK, adenosine monophosphate (AMP)-activated protein kinase; GLUT-4, glucose transporter type 4; GSV, GLUT-4 storage vesicle; AR, androgen receptor3. Graphic created with BioRender.com.