Quantitative proteomics analysis reveals molecular networks regulated by epidermal growth factor receptor level in head and neck cancer

Wei Yang, Quan Cai, Vivian W.Y. Lui, Patrick A. Everley, Jayoung Kim, Neil Bhola, Kelly M. Quesnelle, Bruce R. Zetter, Hanno Steen, Michael R. Freeman, Jennifer R. Grandis

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck cancer (HNC), where increased expression levels of EGFR correlate with poor prognosis. To date, EGFR expression levels have not predicted the clinical response to the EGFR-targeting therapies. Elucidation of the molecular mechanisms underlying anti-EGFR-induced antitumor effects may shed some light on the mechanisms of HNC resistance to EGFR-targeting therapeutics and provide novel targets for improving the treatment of HNC. Here, we conducted a quantitative proteomics analysis to determine the molecular networks regulated by EGFR levels in HNC by specifically knocking-down EGFR and employing stable isotope labeling with amino acids in cell culture (SILAC). Following data normalization to minimize systematic errors and Western blotting validation, 12 proteins (e.g., p21, stratifin, and maspin) and 24 proteins (e.g., cdc2 and MTA2) were found to be significantly upregulated or downregulated by EGFR knockdown, respectively. Bioinformatic analysis revealed that these proteins were mainly involved in long-chain fatty acid biosynthesis and β-oxidation, cholesterol biosynthesis, cell proliferation, DNA replication, and apoptosis. Cell cycle analysis confirmed that G2/M phase progression was significantly inhibited by EGFR knockdown, a hypothesis generated from network modeling. Further investigation of these molecular networks may not only enhance our understanding of the antitumor mechanisms of EGFR targeting but also improve patient selection and provide novel targets for better therapeutics.

Original languageEnglish (US)
Pages (from-to)3073-3082
Number of pages10
JournalJournal of Proteome Research
Volume9
Issue number6
DOIs
StatePublished - Jun 4 2010
Externally publishedYes

Keywords

  • P53 quantitative proteomics
  • cholesterol
  • epidermal growth factor receptor
  • fatty acids
  • head and neck cancer
  • mass spectrometry
  • molecular network
  • small interfering RNA
  • stable isotope labeling with amino acids in cell culture

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry

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