Please use this identifier to cite or link to this item:
http://bura.brunel.ac.uk/handle/2438/13874
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Wagner, R | - |
dc.contributor.author | Stubiger, G | - |
dc.contributor.author | Veigel, D | - |
dc.contributor.author | Wuczkowski, M | - |
dc.contributor.author | Lanzerstorfer, P | - |
dc.contributor.author | Weghuber, J | - |
dc.contributor.author | Karteris, E | - |
dc.contributor.author | Nowikovsky, K | - |
dc.contributor.author | Wilfinger-Lutz, N | - |
dc.contributor.author | Singer, CF | - |
dc.contributor.author | Colomer, R | - |
dc.contributor.author | Benhamu, B | - |
dc.contributor.author | Lopez-Rodriguez, ML | - |
dc.contributor.author | Valent, P | - |
dc.contributor.author | Grunt, TW | - |
dc.date.accessioned | 2017-01-18T10:19:31Z | - |
dc.date.available | 2017-01-10 | - |
dc.date.available | 2017-01-18T10:19:31Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | Oncotarget, 2017 | en_US |
dc.identifier.issn | 1949-2553 | - |
dc.identifier.uri | http://bura.brunel.ac.uk/handle/2438/13874 | - |
dc.description.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. | en_US |
dc.language.iso | en | en_US |
dc.title | Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells | en_US |
dc.type | Article | en_US |
dc.relation.isPartOf | Oncotarget | - |
pubs.publication-status | Accepted | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
FullText.pdf | 3.31 MB | Adobe PDF | View/Open |
Items in BURA are protected by copyright, with all rights reserved, unless otherwise indicated.