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

Abstract

Receptor-interacting protein kinase 3 (RIPK3) can induce necroptosis, apoptosis, or cell proliferation and is silenced in several hematological malignancies. We previously reported that RIPK3 activity independent of its kinase domain induces caspase-mediated p65/RelA cleavage, resulting in N-terminal 1-361 and C-terminal 362-549 fragments. We show here that a noncleavable p65/RelA D361E mutant expressed in DA1-3b leukemia cells decreases mouse survival times and that coexpression of p65/RelA fragments increases the tumorigenicity of B16F1 melanoma cells. This aggressiveness in vivo did not correlate with NF-κB activity measured in vitro. The fragments and p65/RelA D361E mutant induced different expression profiles in DA1-3b and B16F1 cells. Stemness markers were affected: p65/RelA D361E increased ALDH activity in DA1-3b cells, and fragment expression increased melanoma sphere formation in B16/F1 cells. p65/RelA fragments and the D361E noncleavable mutant decreased oxidative or glycolytic cell metabolism, with differences observed between models. Thus, p65/RelA cleavage initiated by kinase-independent RIPK3 activity in cancer cells is not neutral and induces pleiotropic effects in vitro and in vivo that may vary across tumor types.

• Authors: Yasmine Touil, Céline Latreche-Carton, Hassiba El Bouazzati, Anne-Lucie Nugues, Nathalie Jouy, Xavier Thuru, William Laine, Frederic Lepretre, Martin Figeac, Meryem Tardivel, Jérôme Kluza, Thierry Idziorek, Bruno Quesnel
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 123 Issue 3 Pg. 543-556 (03 2022) ISSN: 1097-4644 [Electronic] United States
• PMID: 34927768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals LLC.

Chemical References

• NF-kappa B
• Transcription Factor RelA
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Caspases

Topics

• Animals
• Apoptosis
• Caspases (metabolism)
• Melanoma
• Mice
• NF-kappa B (metabolism)
• Phosphorylation
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism, pharmacology)
• Transcription Factor RelA (genetics, metabolism)