ArticleOncotarget2017
Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 57 citations in OpenAlex.
- Lipogenesis-driven EGFR palmitoylation enables metastatic immune evasion in triple-negative breast cancer.bioRxiv : the preprint server for biology · 2026Article
- Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma.Cell death & disease · 2026Article
- Soft lithography-based biomolecule patterning techniques and their applications in subcellular protein interaction analysis.Materials today. Bio · 2025Review
- New UB006 Derivatives With Higher Solubility and Cytotoxic Activity in Ovarian Cancer Cells.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Fatty acid synthase in chemoresistance: mechanisms and therapeutic opportunities.Frontiers in pharmacology · 2025Review
- Today's cancer research and treatment - highly sophisticated and molecularly targeted, yet firmly bolstered in the classical theories.Journal of applied biomedicine · 2024Review
- Interplay between altered metabolism and DNA damage and repair in ovarian cancer.BioEssays : news and reviews in molecular, cellular and developmental biology · 2024Review
- Targeting endogenous fatty acid synthesis stimulates the migration of ovarian cancer cells to adipocytes and promotes the transport of fatty acids from adipocytes to cancer cells.International journal of oncology · 2024Article
- Unraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways.Frontiers in cell and developmental biology · 2024Review
- Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance.Acta biochimica et biophysica Sinica · 2023Review
- Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies.Molecular therapy oncolytics · 2023Review
- Article
- Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications.International journal of molecular sciences · 2022Review
- Subcellular Dynamic Immunopatterning of Cytosolic Protein Complexes on Microstructured Polymer Substrates.ACS sensors · 2021Article
- Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt.Cell death & disease · 2021Article
- Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity.Molecular cell · 2021Review
- Dual regulation of fatty acid synthase (FASN) expression by O-GlcNAc transferase (OGT) and mTOR pathway in proliferating liver cancer cells.Cellular and molecular life sciences : CMLS · 2021Article
- The Pharmacological or Genetic Blockade of EndogenousFrontiers in oncology · 2021Article
- Membrane disruption, but not metabolic rewiring, is the key mechanism of anticancer-action of FASN-inhibitors: a multi-omics analysis in ovarian cancer.Scientific reports · 2020Article
- Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.