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p65/RelA NF-κB fragments generated by RIPK3 activity regulate tumorigenicity, cell metabolism, and stemness

Yasmine Touil1,2, Céline Latreche-Carton1,2, Hassiba El Bouazzati1,2

  • 1CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.

Journal of Cellular Biochemistry
|December 20, 2021
PubMed

Insights

Receptor-interacting protein kinase 3 (RIPK3) activity cleaves p65/RelA, impacting cancer cell behavior. This cleavage and its fragments influence tumor growth and metabolism, varying by cancer type.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Cancer research

Background:

  • Receptor-interacting protein kinase 3 (RIPK3) regulates cell death and proliferation.
  • RIPK3 is often silenced in hematological malignancies.
  • Kinase-independent RIPK3 activity can cleave p65/RelA, generating specific fragments.

Purpose of the Study:

  • To investigate the functional consequences of p65/RelA cleavage and its fragments induced by RIPK3.
  • To assess the impact of a noncleavable p65/RelA mutant on cancer aggressiveness.
  • To explore the effects on cancer cell metabolism and stemness markers.

Main Methods:

  • Expression of a noncleavable p65/RelA mutant (D361E) in DA1-3b leukemia cells.
  • Coexpression of p65/RelA fragments in B16F1 melanoma cells.
  • Assessment of mouse survival, tumor growth, NF-κB activity, gene expression, stemness markers (ALDH activity, sphere formation), and cellular metabolism (oxidative and glycolytic).

Main Results:

  • The noncleavable p65/RelA D361E mutant decreased mouse survival.
  • Coexpressed p65/RelA fragments increased B16F1 melanoma cell tumorigenicity in vivo.
  • NF-κB activity in vitro did not correlate with in vivo aggressiveness.
  • Both the mutant and fragments altered gene expression profiles and affected stemness markers (ALDH, sphere formation).
  • Metabolic profiles (oxidative and glycolytic) were decreased by p65/RelA fragments and the D361E mutant, with model-specific differences.

Conclusions:

  • p65/RelA cleavage by kinase-independent RIPK3 activity has significant, non-neutral effects on cancer cells.
  • These effects include altered tumorigenicity, stemness, and metabolism, which are pleiotropic and context-dependent.
  • The findings highlight a novel role for RIPK3-mediated p65/RelA cleavage in cancer progression across different tumor types.
Keywords:
RIPK3cancerfragmentp65/RelAstemness

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