Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 123, Issue 3, Pages 543-556Publisher
WILEY
DOI: 10.1002/jcb.30198
Keywords
cancer; fragment; p65; RelA; RIPK3; stemness
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Funding
- Institut National Du Cancer [INCa-DGOS-Inserm 6041aa]
- Institut pour la Recherche sur le Cancer de Lille
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In cancer cells, RIPK3 activity can induce p65/RelA cleavage and affect stemness markers, leading to increased tumor aggressiveness and alterations in cell metabolism.
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-kappa B 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.
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