The Pharmacological or Genetic Blockade of Endogenous De Novo Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells

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.

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“…This made β -oxidation an interesting new target for the treatment of ovarian cancer. At the same time, the inhibitors of fatty acid synthase (encoded by the FASN gene) cause growth arrest and apoptosis in the same type of cells [ 44 ]. FASN is the rate-limiting enzyme of FAS, which is overexpressed in ovarian cancer.…”

Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways

“…The anti-proliferation effect of lipogenesis inhibitors can be augmented by limiting exogenous fatty acid supplementation [104,117]. Efforts have been made to understand the relationship between de novo lipid synthesis and exogenous lipids and determine their particular roles in chemo and radiation therapy resistance [118].…”

Over-Reduced State of Mitochondria as a Trigger of “β-Oxidation Shuttle” in Cancer Cells

“…In 2011, Nieman et al found that co-culturing ovarian cancer cells with human-derived adipocytes resulted in increased β-oxidation by activating CPT1 and acyl-CoA oxidase 1 [ 12 ]. The rate-limiting enzyme of FAS (fatty acid synthase) has been found to be overexpressed in ovarian cancer, whose inhibitors cause growth arrest and apoptosis in the same type of cells [ 13 ].…”