AKT regulates NPM dependent ARF localization and p53mut stability in tumors

Abstract

Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53mut stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53mut status.

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways

“…Therefore, miR302a may have targeted p-ERK1/2 and p-Akt through the MAPK and PI3K signaling pathways, respectively, and this may be its primary contribution to the inhibition of cell proliferation in TE-10 and ECA109 cells. Consistent with previous results, in the present study, the phosphorylation levels of Akt and ERK1/2 were significantly decreased in the miR302a mimics group (P<0.05), and increased in the miR302a inhibitor group (P<0.01) (23)(24)(25)(26). Furthermore, total Akt and ERK1/2 expression levels were also determined by western blot analysis in TE-10 and ECA109 cells, and overexpression of miR302a did not markedly differ between groups.…”

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

“…These data support our hypothesis that the mechanism of p53-dependent hypoxia-induced apoptosis includes AKT inhibition and that this can be exploited in vivo through pharmacological inhibitors. PI3K/AKT inhibitors when combined with radiotherapy (53)(54)(55)(56)(57).…”

A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression

“…164 Smallmolecule inhibitors of phosphatidylinositol 3′-kinase, AKT or prodigiosin disrupt the inhibitory effect of mutant p53 on TAp73. 165,166 T-oligos trigger inherent telomere-based DNAdamage responses and engage TAp73 in p53-deficient melanoma cells. 167 Not to forget is, however, that DNp73 confers GOF uncoupled from any TA-dependent antagonism, 2-4 which probably relies on a hitherto unknown target gene repertoire.…”