Identifying Novel Mechanistic Pathways Underlying Pathogenesis of Endometriosis

Abstract

Background: Endometriosis is the growth of endometrial tissue outside the uterine cavity usually in the ovaries, fallopian tube, and the pelvic cavity. It affects 1 in 10 women which is approximately 176 million women worldwide. Endometriosis is associated with severe pelvic pain, infertility, dysmenorrhea, and dyspareunia. The gold standard for confirmatory diagnosis is through laparoscopy which is not practical as a first diagnostic tool. Defining the molecular etiology of endometriosis is remarkably challenging for improving women’s quality of life. Unfortunately, the pathophysiology of endometriosis remains to be elucidated. CYP4A and its metabolites, 20-HETE, is well known in its role in inflammation and angiogenesis. Further on, mTOR-signaling pathway is well described to be associated with cellular proliferation as well as organ injury through affecting myriads of pathways including inflammatory pathway. Recent research suggests that disrupted kinase signaling pathways and oxidative stress may play a role in proliferation and survival of endometrial cells outside their niches. Furthermore, our lab has previously shown that ROS, NADPH oxidase as well as NOX1 and NOX4 are upregulated in endometriosis. Aim: In this study, we aim to investigate the role of AMPK/CYP4A/mTOR signaling axes in inducing the proliferation of endometriotic implants. Methods: Ex vivo experiments were conducted on anonymous endometriotic tissues collected from women that underwent laparoscopy. Moreover, mTOR, Raptor, AMPK TGF-β and inflammatory cytokines (IL-6, IL-8 and TNF-α) expressions were assessed by PCR and CYP4A expression by western blot. In addition, HPLC was used to measure 20-HETE levels. Histological analysis was also performed. Results: Endometriosis is associated with increased fibrogenesis and inflammatory markers. we postulate that endometrial injury is linked to inactivation of AMPK while mTOR is hyper-regulated. Furthermore, there was significant increase in CYP4A and 20-HETE production that leads to an increase in ROS production. Conclusion. Collectively, our results display the role of AMPK/CYP4A/mTOR signaling axes in the pathogenesis of endometriosis. Therefore, targeting this pathway could be a potential therapeutic approach for the treatment of endometriosis.