Cytoplasmic gain-of-function mutant p53 contributes to inflammation-associated cancer

Abstract

Inflammation and mutation of the tumor suppressor p53 are two apparently unrelated conditions that are strongly associated with cancer initiation and progression. We recently reported that gain-of-function mutant p53 modifies the response of cancer cells to inflammatory signals by binding a cytoplasmic tumor suppressor protein involved in TNFα signaling.

Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions

“…Metformin’s effects on mitigating radiation sensitivity are not limited solely to its anti-oxidant properties, but appears to also be affected by NFκB-mediated survival pathways as evidenced by the lack of a radiation sensitivity modifying effect in SA-NH cells stably transfected with a mutant IκBα vector that inhibits NFκB activation (Murley et al 2004). Since p53 mutations are known to promote cancer progression by augmenting NFκB activation in the context of chronic inflammation and enhance both proinvasive and prosurvival activities, inhibition of NFκB activity in p53 mutant tumor cells should exhibit as profound effect or more than was observed in the p53 WT SA-NH tumor model (Cooks et al 2013; Bellazzo et al, 2015). Prosurvival pathways associated with p53 mutational status and NFκB activation play a determinant role in metformin’s effects on radiation response.…”

p53 gain-of-function mutations promote metastasis via ENTPD5 upregulation and enhanced N-glycoprotein folding

“…4 Mutant p53 GOF activities are manifold and promote, for example, proliferation, drug resistance, immortalization, genomic instability, angiogenesis, stemness, metabolic reprogramming, and inflammation. 1,2,5 In particular, mutp53 augments the propensity for metastatic spreading: numerous in vitro studies demonstrated increased cellular motility and invasiveness upon mutp53 expression, just as genetically-engineered mice expressing mutp53 develop more aggressive and metastatic tumors than p53 knockout animals. While prometastatic activities of mutp53 proteins are now widely acknowledged, the underlying mechanisms are complex and remain incompletely understood.…”

“…Proinflammatory and metabolic activities of mutp53 further contribute to the gain of metastatic potential. 2,5 Although most of these mechanisms function to increase the amount of prometastatic signaling molecules on the cell surface, it seems that not only receptor quantity, but also quality matters. We have observed that mutp53 stimulates the folding of N-glycosylated membrane proteins in the endoplasmic reticulum, thereby it enhances the "quality" of cell surface proteins, which proves essential for its positive effect on motility, invasion, and metastatic lung colonization in vivo.…”