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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Aims Left ventricular hypertrabeculation/non-compaction (LVHT) is a cardiac abnormality of unknown pathogenesis and frequently associated with neuromuscular disorders. The N-terminal fragment of the pro brain natriuretic peptide (NT-pro-BNP) is a prognostic marker in heart failure whose relevance in LVHT patients is largely unknown. The aim of the study was to assess the role of NT-pro-BNP levels as prognostic markers in LVHT. Methods and results Data of LVHT patients were collected in a database from one echocardiographic laboratory since 1996. The hospital information system was screened for measurements of NT-pro-BNP levels, and their association with clinical and echocardiographic baseline parameters was retrospectively assessed. During follow-up, the endpoints were death and heart transplantation. In 113 patients (median age 57 years, 24% women), data about NT-pro-BNP measurements were found, ranging from 8 to 121 152 (median 2029) ng/L. High NT-pro-BNP levels were associated with heart failure, valvular abnormalities, diabetes mellitus, hypertension, angina pectoris, number of LVHT-affected segments, end-diastolic diameter, and systolic dysfunction. During a follow-up of 73 (±64; 0-237) months, 35% of the patients reached an endpoint. High NT-pro-BNP levels were associated with the occurrence of an endpoint (P < 0.001). By multivariate analysis, predictors for endpoints were increased age (P = 0.0025), atrial fibrillation (P = 0.0023), natural logarithm of NT-pro-BNP levels (P = 0.0073), diabetes mellitus (P = 0.014), and thromboembolic events before diagnosis (P = 0.0347). Conclusions Also in LVHT patients, high NT-pro-BNP levels are indicators for death and heart transplantation.