P65/RelA NF‐κB fragments generated by RIPK3 activity regulate tumorigenicity, cell metabolism, and stemness characteristics. Issue 3 (20th December 2021)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of cellular biochemistry. Volume 123:Issue 3(2022)
• Page Start: 543
• Page End: 556
• Publication Date: 2021-12-20
• Subjects: cancer -- fragment -- p65/RelA -- RIPK3 -- stemness; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.30198
• Languages: English
• ISSNs: 0730-2312

Abstract

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.