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Role Of S-Nitrosylation In The Extrinsic Apoptotic Signalling Pathway In Cancer

Stéphanie Plenchette1

  • 1Laboratoire d'Immunologie et Immunothérapie des Cancers, EPHE-Université de Bourgogne EA 7269, Faculté de Médecine, Dijon, France.

Redox Biology
|February 7, 2017
PubMed

Insights

Tumor cells resist apoptosis, hindering cancer treatment. Nitric oxide (NO) modification, specifically S-nitrosylation, of death receptors like Fas can trigger apoptosis, offering a potential therapeutic strategy for tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Tumor cells often develop resistance to apoptosis, a programmed cell death mechanism, posing a significant challenge for cancer therapy.
  • Activating death receptor signaling pathways is a key strategy to overcome apoptotic resistance and induce tumor regression.
  • Tumor Necrosis Factor (TNF)-family death receptor ligands, such as TRAIL, FasL, and TNF-α, play crucial roles in initiating cell death signaling.

Purpose of the Study:

  • To investigate the role of post-translational modifications, particularly S-nitrosylation, in regulating TNF-family death receptor signaling pathways.
  • To explore how nitric oxide (NO) influences cell fate decisions in tumor cells exposed to death receptor ligands.
  • To elucidate the molecular mechanisms by which S-nitrosylation of death receptors promotes apoptosis and tumor regression.

Main Methods:

  • Examining the S-nitrosylation of death receptors (DR4 and Fas) following treatment with NO donors or glyceryl trinitrate (GTN).
  • Analyzing the effect of S-nitrosylation on the redistribution of Fas to lipid rafts and the formation of the death-inducing signal complex (DISC).
  • Investigating the regulatory mechanisms of the TNF-α/TNFR1 signaling pathway by S-nitrosylation.

Main Results:

  • S-nitrosylation of death receptor DR4 promotes apoptosis upon treatment with an NO donor.
  • S-nitrosylation of Fas, induced by glyceryl trinitrate (GTN), facilitates its redistribution to lipid rafts and DISC formation, leading to apoptosis.
  • S-nitrosylation emerges as a critical post-translational modification controlling cell fate in TNF-family death receptor signaling.

Conclusions:

  • S-nitrosylation is a key regulatory mechanism in TNF-family death receptor signaling pathways.
  • Targeting S-nitrosylation of death receptors presents a promising therapeutic strategy to overcome apoptotic resistance in tumors.
  • Further research into NO-mediated regulation of TNF-α/TNFR1 signaling could uncover novel anti-cancer treatments.

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