Abstract
Ovarian cancer(OC) is a serious threat to women worldwide. Peritoneal dissemination, ascites and omental metastasis are typical features for disease progression, which occurs in a micro-environment that is rich in high-energy lipids. OC cells require high amounts of lipids for survival and growth. Not only do they import lipids from the host, they also produce lipids de novo. Inhibitors of fatty acid(FA) synthase(FASN) – the rate-limiting enzyme of endogenous FA synthesis that is overexpressed in OC – induce growth-arrest and apoptosis, rendering them promising candidates for cancer drug development. However, cancer researchers have long hypothesized that the lipid deficiency caused by FASN inhibition can be circumvented by increasing the uptake of exogenous lipids from the host, which would confer resistance to FASN inhibitors. In contrast to a very recent report in colorectal cancer, we demonstrate in OC cells (A2780, OVCAR3, SKOV3) that neither FASN inhibitors (G28UCM, Fasnall) nor FASN-specific siRNAs can stimulate a relief pathway leading to enhanced uptake of extrinsic FAs or low density lipoproteins (LDLs). Instead, we observed that the growth-arrest due to FASN inhibition or FASN knock-down was associated with significant dose- and time-dependent reduction in the uptake of fluorescently labeled FAs and LDLs. Western blotting showed that the expression of the FA receptor CD36, the LDL receptor(LDLR) and the lipid transport proteins fatty acid binding proteins 1–9 (FABP1–9) was not affected by the treatment. Next, we compared experimental blockade of endogenous lipid production with physiologic depletion of exogenous lipids. Lipid-free media, similar to FASN inhibitors, caused growth-arrest. Although lipid-depleted cells have diminished amounts of CD36, LDLR and FABPs, they can still activate a restorative pathway that causes enhanced import of fluorophore-labeled FAs and LDLs. Overall, our data show that OC cells are strictly lipid-depend and exquisitely sensitive to FASN inhibitors, providing a strong rationale for developing anti-FASN strategies for clinical use against OC.
Highlights
With more than 140,200 deaths every year, ovarian cancer (OC) represents the most lethal malignancy of the female reproductive tract worldwide [1, 2]
In accordance with previous reports [2, 21, 22] we show that disabling fatty acid synthase (FASN) reduces OC cell growth
Specific alterations in the lipid metabolism, for example, cause both activation of de novo synthesis of endogenous FA and import of exogenous FA. This enables the malignant cells to cope with the high demand for lipids, which serve as building blocks for new membranes, as signaling molecules and as vehicles for bioenergy for growth, migration, invasion and metastasis [4, 29, 30]
Summary
With more than 140,200 deaths every year, ovarian cancer (OC) represents the most lethal malignancy of the female reproductive tract worldwide [1, 2]. Advanced-stage OC usually spreads to the abdominal cavity and results in floating cells that condition the peritoneal epithelium to produce large volumes of ascites This fluid typically contains high-energy nutrients like FA and lipids, which can support the growth of OC cells [4]. Cancer cells exposed to FASN blockers can, activate regulatory bypass loops that compensate for the ceased endogenous lipid supply While this has not been shown directly until recently, the efficacy of FASN inhibitory drugs could be compromised by activating pathways that stimulate the uptake of extracellular FAs and lipids [11, 12]. Instead, when given continuously over one or two days, they rather diminish FA- and lipid-import It appears that stimulation of dietary lipid uptake is not an important mechanism for resistance of OC to FASN inhibitors. These finding will be important for future clinical trials with antiFASN drugs
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