Effects of dual inhibition of AKT and ERK1/2 pathways on endometrial pro-inflammatory, hormonal, and epigenetic microenvironment in endometriosis

Arosh JA, Joe A. Arosh, JeHoon Lee, Banu SK, Sakhila K. Banu
Molecular and cellular endocrinology · 2021 · vol. 539 , pp. 111446 · doi:10.1016/j.mce.2021.111446 · PMID:34478807 · W3198834199
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This study investigated how blocking AKT and ERK1/2 pathways impacts the pro-inflammatory, hormonal, and epigenetic environment within endometriosis lesions.

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Abstract

Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. The prevalence of endometriosis is ~5-10% in reproductive-age women, increasing to 20-30% in women with subfertility. The current anti-estrogen therapies can be prescribed only for a short time because of the undesirable side effects on menstruation, pregnancy, bone health, and failure to prevent a recurrence. The causes of endometriosis-associated infertility are multifactorial and poorly understood. The objective of the present study was to determine the inhibitory effects of AKT and/or ERK1/2 pathways on the microenvironment of the endometrium in a xenograft mouse model of endometriosis of human origin. Results indicate that dual inhibition of AKT and ERK1/2 pathways, but not inhibition of either AKT or ERK1/2 pathway, suppresses the growth of the endometriotic lesions in vivo. Dual inhibition of AKT and ERK1/2 pathways suppresses the production of proinflammatory cytokines, decreases E2 biosynthesis and signaling, and restores progesterone receptor-B signaling components in the epithelial and stromal cells of the endometrium in a cell-specific manner. These results together suggest that dual inhibition of AKT and ERK1/2 pathways suppresses the estrogen-dominant state and concomitantly increases the progesterone-responsive state of the endometrium. Therefore, dual inhibition of AKT and ERK1/2 pathways could emerge as long-term nonsteroidal therapy for endometriosis.

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Condition tags

endometriosis

MeSH descriptors

Butadienes Chromones Endometriosis MAP Kinase Signaling System Morpholines Nitriles Proto-Oncogene Proteins c-akt Animals Butadienes Butadienes Cell Line Cell Proliferation Cell Proliferation Cell Survival Cell Survival Chromones Chromones Cytokines Cytokines Disease Models, Animal

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

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