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

Rogers‑Broadway,Karly‑Rai; Kumar,Juhi; Sisu,Cristina; Wander,Gurleen; Mazey,Emily; Jeyaneethi,Jeyarooban; Pados,George; Tsolakidis,Dimitris; Klonos,Eleftherios; Grunt,Thomas; Hall,Marcia; Chatterjee,Jayanta; Karteris,Emmanouil

doi:10.3892/ijmm.2018.3967

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

Authors:
- Karly‑Rai Rogers‑Broadway
- Juhi Kumar
- Cristina Sisu
- Gurleen Wander
- Emily Mazey
- Jeyarooban Jeyaneethi
- George Pados
- Dimitris Tsolakidis
- Eleftherios Klonos
- Thomas Grunt
- Marcia Hall
- Jayanta Chatterjee
- Emmanouil Karteris
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Affiliations: Division of Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK, Queen Charlotte and Chelsea Hospital, London W120HS, UK, First Department of OB‑GYN, ‘Papageorgiou’ Hospital, University of Thessaloniki Medical School, Thessaloniki 54124, Greece, Ludwig Boltzmann Cluster Oncology and Division of Oncology, Department of Medicine I, Medical University Vienna, A‑1090 Vienna, Austria, Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, Surrey GU2 7XH, UK
Published online on: October 31, 2018 https://doi.org/10.3892/ijmm.2018.3967
Pages: 47-56
Copyright: © Rogers‑Broadway et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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