Differential expression of mTOR components in endometriosis and ovarian cancer: Effects of rapalogues and dual kinase inhibitors on mTORC1 and mTORC2 stoichiometry

Abstract

Endometriosis is a well-known risk factor for ovarian cancer. The genetic changes that characterise endometriosis are poorly understood; however, the mechanistic target of rapamycin (mTOR) pathway is involved. In this study, we investigated the expression of key mTOR components in endometriosis and the effects of rapalogues using an endometrioid ovarian carcinoma cell line (MDAH 2774) as an in vitro model. Gene expression of mTOR, DEPTOR, Rictor and Raptor was assessed by qPCR in 24 endometriosis patients and in silico in ovarian cancer patients. Furthermore, the effects of Rapamycin, Everolimus, Deforolimus, Temsirolimus, Resveratrol, and BEZ235 (Dactolisib, a dual kinase inhibitor) on mTOR signalling components was assessed. mTOR showed a significant increase in the expression in endometriosis and ovarian endometrioid adenocarcinoma patients compared to non-affected controls. DEPTOR, an inhibitor of mTOR, was downregulated in the advanced stages of ovarian cancer (III and IV) compared to earlier stages (I and II). Treatment of MDAH-2774 cells with the mTOR inhibitors resulted in the significant upregulation of DEPTOR mRNA, whereas treatment with rapamycin and BEZ-235 (100 nM) resulted in downregulation of the mTOR protein expression after 48 h of treatment. None of the treatments resulted in translocation of mTOR from cytoplasm to nucleus. Upregulation of DEPTOR is a positive prognostic marker in ovarian cancer and is increased in response to mTOR pathway inhibition suggesting that it functions as a tumour suppressor gene in endometrioid ovarian carcinoma. Collectively, our data suggest the mTOR pathway as a potential connection between endometriosis and ovarian cancer and may be a potential target in the treatment of both conditions.

Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I-II and III-IV endometriosis independently of hormonal milieu

“…Additionally, these pathways are also extensively reported in other processes such as immunosurveillance 157 , stem cell self-renewal 158 and epithelial to mesenchymal transition 159 . Some of these processes have already been described in endometriosis pathogenesis and they include Kras signalling 160,161 , MYC targets 162,163 , mTORC1 signalling [164][165][166] , PI3K AKT mTOR signalling [167][168][169][170] , TGF beta signalling [171][172][173] , interferon gamma [174][175][176][177] , and interferon alpha response 178,179 . In accordance with our data regarding microenvironment heterogeneity, certain pathways that are enriched in the stage III-IV phenotype are directly associated to M1-M2 macrophage polarization, and these pathways include TGF beta sinalling 180,181 , PI3K AKT mTOR signalling 151,182 , interferon gamma response 79 , adipogenesis, glycolysis and other metabolic reprograming pathways 183 .…”

The role of ubiquitination and deubiquitination in cancer metabolism

“…Aberrant activation of mTORC1 is considered as a key feature of metabolic reprogramming. mTORC1 is a complex consisting of mTOR, Raptor, mLST8, PRAS40 and DEPTOR [ 39 ]. mTOR is an evolutionarily conserved serine/threonine protein kinase in the PI3K-related kinase superfamily, responsible for the catalytic activity of mTORC1 [ 40 ].…”

H2A Histone Family Member X (H2AX) Is Upregulated in Ovarian Cancer and Demonstrates Utility as a Prognostic Biomarker in Terms of Overall Survival

“…We demonstrate that the OC population with high H2AX expression is associated with upregulation of several biological pathways, such as PI3K/AKT/mTOR, activated in~50% serous OC [22]. This pathway, and primarily the mTORC1 complex, provides a balance between cellular resources such as amino acids and/or cellular stressors such as hypoxia to control cellular behaviour [23]. Emerging data also links mTOR with the aetiopathogenesis of OC.…”