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, Christian Singer, Ramon Colomer, Bellinda Benhamu, Maria Lopez-Rodrguez, Peter Valent, Thomas Grunt

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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-1a-REDD1 (RTP801/DIG2/DDIT4) and AMPKa 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/mTORinhibitor 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.

Original languageEnglish
Pages (from-to)11600-11613
Number of pages14
JournalOncotarget
Volume8
Issue number7
DOIs
Publication statusPublished - Feb 2017

Keywords

  • AMPK
  • Fatty acid synthase (FASN)
  • Lipids
  • MTORC1
  • REDD1
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction
  • Humans
  • Cell Proliferation/physiology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Enzyme Inhibitors/pharmacology
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • Ovarian Neoplasms/drug therapy
  • Fatty Acid Synthases/antagonists & inhibitors
  • Cell Line, Tumor
  • Female
  • Multiprotein Complexes/antagonists & inhibitors

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