Oncotarget

Research Papers:

Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells

Renate Wagner, Gerald Stübiger, Daniel Veigel, Michael Wuczkowski, Peter Lanzerstorfer, Julian Weghuber, Emmanouil Karteris, Karin Nowikovsky, Nastasia Wilfinger-Lutz, Christian F. Singer, Ramón Colomer, Bellinda Benhamú, María Luz López-Rodríguez, Peter Valent and Thomas W. Grunt _

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Oncotarget. 2017; 8:11600-11613. https://doi.org/10.18632/oncotarget.14591

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Abstract

Renate Wagner1,2, Gerald Stübiger2,3,4, Daniel Veigel1,2, Michael Wuczkowski3,4, Peter Lanzerstorfer5, Julian Weghuber5, Emmanouil Karteris6, Karin Nowikovsky1,2, Nastasia Wilfinger-Lutz1,2, Christian F. Singer7, Ramón Colomer8, Bellinda Benhamú9, María Luz López-Rodríguez9, Peter Valent2,10,11, Thomas W. Grunt1,2,11

1Division of Oncology, Department of Medicine I, Medical University Vienna, Vienna, Austria

2Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria

3Department of Biomedical Imaging and Image-guided Therapy, Medical University Vienna, Vienna, Austria

4Center for Biomarker Research in Medicine, Graz, Austria

5University of Applied Sciences Upper Austria, School of Engineering and Environmental Sciences, Wels, Austria

6Department of Biosciences, School of Health Sciences and Social Care, Brunel University London, Uxbridge, UK

7Department of Obstetrics/Gynecology, Medical University Vienna, Vienna, Austria

8Department of Medical Oncology, Hospital Universitario La Princesa and Spanish National Cancer Research Center (CNIO), Clinical Research Program, Madrid, Spain

9Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Madrid, Spain

10Division of Hematology and Hemostaseology, Department of Medicine I, Medical University Vienna, Vienna, Austria

11Ludwig Boltzmann Cluster Oncology, Medical University Vienna, Vienna, Austria

Correspondence to:

Thomas W. Grunt, email: [email protected]

Keywords: AMPK, fatty acid synthase (FASN), lipids, mTORC1, REDD1

Received: February 24, 2016     Accepted: December 24, 2016     Published: January 10, 2017

ABSTRACT

Receptor-PI3K-mTORC1 signaling and fatty acid synthase (FASN)-regulated lipid biosynthesis harbor numerous drug targets and are molecularly connected. We hypothesize that unraveling the mechanisms of pathway cross-talk will be useful for designing novel co-targeting strategies for ovarian cancer (OC). The impact of receptor-PI3K-mTORC1 onto FASN is already well-characterized. However, reverse actions–from FASN towards receptor-PI3K-mTORC1–are still elusive. We show that FASN-blockade impairs receptor-PI3K-mTORC1 signaling at multiple levels. Thin-layer chromatography and MALDI-MS/MS reveals that FASN-inhibitors (C75, G28UCM) augment polyunsaturated fatty acids and diminish signaling lipids diacylglycerol (DAG) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in OC cells (SKOV3, OVCAR-3, A2780, HOC-7). Western blotting and micropatterning demonstrate that FASN-blockers impair phosphorylation/expression of EGF-receptor/ERBB/HER and decrease GRB2–EGF-receptor recruitment leading to PI3K-AKT suppression. FASN-inhibitors activate stress response-genes HIF-1α-REDD1 (RTP801/DIG2/DDIT4) and AMPKα causing mTORC1- and S6-repression. We conclude that FASN-inhibitor-mediated blockade of receptor-PI3K-mTORC1 occurs due to a number of distinct but cooperating processes. Moreover, decrease of PI3K-mTORC1 abolishes cross-repression of MEK-ERK causing ERK activation. Consequently, the MEK-inhibitor selumetinib/AZD6244, in contrast to the PI3K/mTOR-inhibitor dactolisib/NVP-BEZ235, increases growth inhibition when given together with a FASN-blocker. We are the first to provide deep insight on how FASN-inhibition blocks ERBB-PI3K-mTORC1 activity at multiple molecular levels. Moreover, our data encourage therapeutic approaches using FASN-antagonists together with MEK-ERK-inhibitors.


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