TY - JOUR
T1 - Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells
AU - Wagner, Renate
AU - Stübiger, Gerald
AU - Veigel, Daniel
AU - Wuczkowski, Michael
AU - Lanzerstorfer, Peter
AU - Weghuber, Julian
AU - Karteris, Emmanouil
AU - Nowikovsky, Karin
AU - Wilfinger, Nastasia
AU - Singer, Christian
AU - Colomer, Ramon
AU - Benhamu, Bellinda
AU - Lopez-Rodrguez, Maria
AU - Valent, Peter
AU - Grunt, Thomas
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
KW - AMPK
KW - Fatty acid synthase (FASN)
KW - Lipids
KW - MTORC1
KW - REDD1
KW - Phosphoinositide-3 Kinase Inhibitors
KW - Signal Transduction
KW - Humans
KW - Cell Proliferation/physiology
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Enzyme Inhibitors/pharmacology
KW - Mechanistic Target of Rapamycin Complex 1
KW - TOR Serine-Threonine Kinases/antagonists & inhibitors
KW - Ovarian Neoplasms/drug therapy
KW - Fatty Acid Synthases/antagonists & inhibitors
KW - Cell Line, Tumor
KW - Female
KW - Multiprotein Complexes/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85012874050&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.14591
DO - 10.18632/oncotarget.14591
M3 - Article
C2 - 28086243
VL - 8
SP - 11600
EP - 11613
JO - Oncotarget
JF - Oncotarget
IS - 7
ER -