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

• Published in: Journal of cellular biochemistry 2022-03, Vol.123 (3), p.543-556
• Main Authors: Touil, Yasmine, Latreche‐Carton, Céline, Bouazzati, Hassiba El, Nugues, Anne‐Lucie, Jouy, Nathalie, Thuru, Xavier, Laine, William, Lepretre, Frederic, Figeac, Martin, Tardivel, Meryem, Kluza, Jérôme, Idziorek, Thierry, Quesnel, Bruno
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biochemistry, Molecular Biology; Cancer; Caspase; Caspases - metabolism; Cell proliferation; Cellular Biology; Cleavage; fragment; Fragments; Glycolysis; Kinases; Leukemia; Life Sciences; Melanoma; Metabolism; Mice; Mutants; Necroptosis; NF-kappa B - metabolism; Oxidative metabolism; p65/RelA; Phosphorylation; Protein kinase; Protein turnover; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - pharmacology; RelA protein; RIPK3; stemness; Subcellular Processes; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Tumorigenicity; Tumors
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.30198

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.