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Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation

Daehyeon Seong1, Manhyung Jeong1, Jinho Seo1,2

  • 1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 120-749 Seoul, Republic of Korea.

Proceedings of the National Academy of Sciences of the United States of America
|August 6, 2020
PubMed

Insights

The oncogene MYC suppresses necroptosis, a cell death pathway crucial in cancer. Inhibiting MYC promotes necroptosis, offering a potential cancer therapy strategy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Death Mechanisms

Background:

  • The role of necroptosis in cancer pathogenesis remains incompletely understood.
  • Identifying regulators of necroptosis is critical for developing novel cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism by which the oncogene MYC influences necroptosis.
  • To investigate MYC's potential as a therapeutic target for inducing necroptosis in cancer.

Main Methods:

  • Gene set enrichment analysis to identify dysregulated pathways during necroptosis.
  • In vitro binding assays to assess MYC-RIPK3 and RIPK1-RIPK3 interactions.
  • Cellular experiments involving MYC depletion/deletion and MYC-nick expression.
  • In vivo xenograft studies using cancer cell lines treated with necroptosis-inducing agents.

Main Results:

  • MYC acts as an antinecroptotic factor by directly inhibiting the formation of the RIPK1-RIPK3 complex.
  • MYC depletion or deletion enhances RIPK1-RIPK3 interaction and promotes necroptosis.
  • MYC binds to RIPK3 in the cytoplasm, preventing RIPK1-RIPK3 complex formation.
  • Down-regulation of MYC sensitizes leukemia cells to necroptosis and suppresses tumor growth in vivo.

Conclusions:

  • MYC-mediated suppression of necroptosis is a key mechanism of resistance in cancer.
  • Targeting MYC to induce necroptosis presents a promising therapeutic strategy for cancer treatment.
Keywords:
MYCRIPK3TNF-αnecroptosis

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