Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

Arvin M. Gouw, Livia S. Eberlin, Katherine Margulis, Delaney K. Sullivan, Georgia G. Toal, Ling Tong, Richard N. Zare*, Dean W. Felsher

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

KRAS gene mutation causes lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, we show that KRAS activates lipogenesis, and this activation results in distinct proteomic and lipid signatures. By gene expression analysis, KRAS is shown to be associated with a lipogenesis gene signature and specific induction of fatty acid synthase (FASN). Through desorption electrospray ionization MS imaging (DESI-MSI), specific changes in lipogenesis and specific lipids are identified. By the nanoimmunoassay (NIA), KRAS is found to activate the protein ERK2, whereas ERK1 activation is found in non-KRAS-associated human lung tumors. The inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cellular proliferation of KRAS-associated lung cancer cells. Hence, KRAS is associated with activation of ERK2, induction of FASN, and promotion of lipogenesis. FASN may be a unique target for KRASassociated lung adenocarcinoma remediation.

Original languageAmerican English
Pages (from-to)4300-4305
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number17
DOIs
StatePublished - 25 Apr 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank Harold Varmus for the CCSP-rtTA/TetOKRAS4bG12D bitransgenic mice, and are grateful to Translational Applications Service Center at Stanford for the Nano Immuno Assay experiments. A.M.G. and K.M. acknowledge Stanford Cancer Translational Nanotechnology Training T32 Training Grant T32 CA196585 funded by the National Cancer Institute and the Stanford Center of Molecular Analysis and Design, respectively. This work is supported by NIH Grant R01CA184384.

Keywords

  • Fatty acid synthase
  • KRAS
  • Lipogenesis
  • Lung
  • MS

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