title: Inhibition of fatty acid synthase induces pro-survival Akt and ERK signaling in K-Ras-driven cancer cells.
abstract: Cancer cells with constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation have been associated with overexpression of the lipogenic enzyme fatty acid synthase (FAS) as a means to provide lipids necessary for cell growth. In contrast, K-Ras-driven cancer cells suppress utilization of de novo synthesized fatty acids and rely on exogenously supplied fatty acids for cell growth and membrane phospholipid biosynthesis. Consistent with a differential need for de novo fatty acid synthesis, cancer cells with activated PI3K signaling were sensitive to suppression of FAS; whereas mutant K-Ras-driven cancer cells continued to proliferate with suppressed FAS. Surprisingly, in response to FAS suppression, we observed robust increases in both Akt and ERK phosphorylation. Akt phosphorylation was dependent on the insulin-like growth factor-1 receptor (IGF-1R)/PI3K pathway and mTOR complex 2. Intriguingly, K-Ras-mediated ERK activation was dependent on N-Ras. Pharmacological inhibition of PI3K and MEK in K-Ras-driven cancer cells resulted in increased sensitivity to FAS inhibition. These data reveal a surprising sensitivity of K-Ras-driven cancer cells to FAS suppression when stimulation of Akt and ERK was prevented. As K-Ras-driven cancers are notoriously difficult to treat, these findings have therapeutic implications.
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, NY, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Yellen
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, NY, USA. Electronic address: foster@genectr.hunter.cuny.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002569:Cerulenin / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D050155:Lipogenesis; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D001549:Benzamides; D002569:Cerulenin; D002867:Chromones; D004159:Diphenylamine; D064429:Fatty Acid Synthases; D054872:Fatty Acid Synthesis Inhibitors; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C117307:KRAS protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C506614:mirdametinib
keywords: Akt; ERK; Fatty acid synthase; K-Ras
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