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

doi:10.1073/pnas.1617709114

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 journal › Article › peer-review

114 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 language	English
Pages (from-to)	4300-4305
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	17
DOIs	https://doi.org/10.1073/pnas.1617709114
State	Published - 25 Apr 2017
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1617709114

Cite this

Gouw, A. M., Eberlin, L. S., Margulis, K., Sullivan, D. K., Toal, G. G., Tong, L., Zare, R. N., & Felsher, D. W. (2017). Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 114(17), 4300-4305. https://doi.org/10.1073/pnas.1617709114

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

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.",

keywords = "Fatty acid synthase, KRAS, Lipogenesis, Lung, MS",

author = "Gouw, {Arvin M.} and Eberlin, {Livia S.} and Katherine Margulis and Sullivan, {Delaney K.} and Toal, {Georgia G.} and Ling Tong and Zare, {Richard N.} and Felsher, {Dean W.}",

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.",

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doi = "10.1073/pnas.1617709114",

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Gouw, AM, Eberlin, LS, Margulis, K, Sullivan, DK, Toal, GG, Tong, L, Zare, RN & Felsher, DW 2017, 'Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 17, pp. 4300-4305. https://doi.org/10.1073/pnas.1617709114

Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. / Gouw, Arvin M.; Eberlin, Livia S.; Margulis, Katherine et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 17, 25.04.2017, p. 4300-4305.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

AU - Gouw, Arvin M.

AU - Eberlin, Livia S.

AU - Margulis, Katherine

AU - Sullivan, Delaney K.

AU - Toal, Georgia G.

AU - Tong, Ling

AU - Zare, Richard N.

AU - Felsher, Dean W.

N1 - 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.

PY - 2017/4/25

Y1 - 2017/4/25

N2 - 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.

AB - 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.

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KW - KRAS

KW - Lipogenesis

KW - Lung

KW - MS

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U2 - 10.1073/pnas.1617709114

DO - 10.1073/pnas.1617709114

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C2 - 28400509

AN - SCOPUS:85018825529

SN - 0027-8424

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EP - 4305

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 17

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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