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GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation

Salvatore Rizza1, Luca Di Leo2, Chiara Pecorari1

  • 1Redox Biology, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.

Cell Reports
|January 19, 2023
PubMed

Insights

S-nitrosoglutathione reductase (GSNOR) deficiency promotes cancer by enabling focal adhesion kinase 1 (FAK1) S-nitrosylation, leading to anoikis resistance. GSNOR acts as a tumor suppressor, and its low expression is a therapeutic target in cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Nitric oxide (NO) and S-nitrosylation are implicated in cancer progression.
  • The specific oncoproteins regulated by S-nitrosylation remain largely unidentified.
  • S-nitrosoglutathione reductase (GSNOR) deactivates S-nitrosylation.

Purpose of the Study:

  • To investigate the role of GSNOR in cancer.
  • To identify oncoproteins regulated by S-nitrosylation in the tumor microenvironment.
  • To explore the therapeutic implications of GSNOR hypo-expression.

Main Methods:

  • Analysis of GSNOR expression in human malignancies.
  • Utilizing multiple tumor models to study GSNOR deficiency.
  • Investigating the S-nitrosylation of focal adhesion kinase 1 (FAK1) at cysteine 658 (C658).
  • Assessing the impact of S-nitrosylation on FAK1 autophosphorylation and anoikis resistance.
  • Evaluating the efficacy of FAK1 inhibitors in GSNOR-deficient tumor models.

Main Results:

  • GSNOR is hypo-expressed in several human cancers.
  • GSNOR deficiency leads to S-nitrosylation of FAK1 at C658.
  • FAK1 S-nitrosylation enhances its autophosphorylation, promoting anoikis resistance and tumorigenicity.
  • GSNOR-deficient tumors exhibit increased susceptibility to FAK1 inhibitors.

Conclusions:

  • GSNOR functions as a tumor suppressor by preventing oncogenic S-nitrosylation.
  • GSNOR hypo-expression is a critical vulnerability in cancer, driving tumorigenesis through FAK1.
  • Targeting FAK1 in cancers with low GSNOR expression represents a promising therapeutic strategy.
Keywords:
CP: CancerCP: Molecular biologyFAK inhibitorsS-nitrosylationSRCanoikiscancerfocal adhesionnitric oxidespheroids

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