Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells

Peter F. Doubleday; Luca Fornelli; Ioanna Ntai; Neil L. Kelleher

doi:10.1111/febs.16111

Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells

Peter F. Doubleday, Luca Fornelli, Ioanna Ntai, Neil L. Kelleher^*

^*Corresponding author for this work

Molecular Biosciences

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

6 Scopus citations

Abstract

Oncogenic mutations in the KRAS gene are found in 30–50% of colorectal cancers (CRC), and recent findings have demonstrated independent and nonredundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that the expression of KRAS^G13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS, and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1 supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.

Original language	English (US)
Pages (from-to)	6683-6699
Number of pages	17
Journal	FEBS Journal
Volume	288
Issue number	23
DOIs	https://doi.org/10.1111/febs.16111
State	Published - Dec 2021

Keywords

aspartate
colorectal cancer
metabolomics
mutant KRAS
quantitative proteomics
urea cycle

ASJC Scopus subject areas

Molecular Biology
Biochemistry
Cell Biology

UN SDGs

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

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10.1111/febs.16111

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title = "Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells",

abstract = "Oncogenic mutations in the KRAS gene are found in 30–50% of colorectal cancers (CRC), and recent findings have demonstrated independent and nonredundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that the expression of KRASG13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS, and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1 supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.",

keywords = "aspartate, colorectal cancer, metabolomics, mutant KRAS, quantitative proteomics, urea cycle",

author = "Doubleday, {Peter F.} and Luca Fornelli and Ioanna Ntai and Kelleher, {Neil L.}",

note = "Funding Information: This research was carried out with support from the National Resource for Translational and Developmental Proteomics under Grant P41 GM108569 from the National Institute of General Medical Sciences (NLK) and supported by the Sherman Fairchild Foundation. PFD acknowledges a NSF Fellowship under award number 2015210477, and the authors thank Emily Bojas and Henry Rodriguez for support in accessing proteomic data and isogenic cell lines from the National Cancer Institute (Office of Cancer Clinical Proteomics Research), National Institutes of Health, under Contract No. HHSN261200800001E. Publisher Copyright: {\textcopyright} 2021 Federation of European Biochemical Societies",

year = "2021",

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doi = "10.1111/febs.16111",

language = "English (US)",

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AU - Doubleday, Peter F.

AU - Fornelli, Luca

AU - Ntai, Ioanna

AU - Kelleher, Neil L.

N1 - Funding Information: This research was carried out with support from the National Resource for Translational and Developmental Proteomics under Grant P41 GM108569 from the National Institute of General Medical Sciences (NLK) and supported by the Sherman Fairchild Foundation. PFD acknowledges a NSF Fellowship under award number 2015210477, and the authors thank Emily Bojas and Henry Rodriguez for support in accessing proteomic data and isogenic cell lines from the National Cancer Institute (Office of Cancer Clinical Proteomics Research), National Institutes of Health, under Contract No. HHSN261200800001E. Publisher Copyright: © 2021 Federation of European Biochemical Societies

PY - 2021/12

Y1 - 2021/12

N2 - Oncogenic mutations in the KRAS gene are found in 30–50% of colorectal cancers (CRC), and recent findings have demonstrated independent and nonredundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that the expression of KRASG13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS, and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1 supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.

AB - Oncogenic mutations in the KRAS gene are found in 30–50% of colorectal cancers (CRC), and recent findings have demonstrated independent and nonredundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that the expression of KRASG13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS, and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1 supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.

KW - aspartate

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KW - metabolomics

KW - mutant KRAS

KW - quantitative proteomics

KW - urea cycle

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Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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