Annexin A2 regulates AKT upon H2O2-dependent signaling activation in cancer cells

Stéphanie Anais Castaldo, Tom Ajime, Gisela Serrão, Fábio Anastácio, Joana Teixeira Rosa, Carman Anthony Giacomantonio, Alison Howarth, Richard Hill, Patrícia Alexandra Madureira

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Abstract

Hydrogen peroxide (H₂O₂) is a main second messenger in oncogenic signaling networks including the Ras and the growth factor receptor pathways. This is achieved predominantly through the oxidation of redox-sensitive cysteine (Cys) residues in proteins resulting in changes to their structure and function. We previously identified annexin A2 (ANXA2) as a redox regulatory protein that plays an important cellular role during oxidative stress and also promoting tumorigenesis. Here we investigated the role of ANXA2 in the regulation of H₂O₂-dependent signaling that drives tumor progression. We show that depletion of ANXA2 leads to the enhanced activation of AKT following either EGF/EGFR stimulation or oncogenic Ras transformation. The phosphatase and tensin homologue (PTEN) protein negatively regulates the PI3K/AKT pathway. We demonstrate that ANXA2 via its reactive Cys-8 residue, binds to PTEN and that the co-expression of PTEN and ANXA2, but not ANXA2 Cys-8-Ala mutant, inhibits AKT phosphorylation on Ser 473. These results indicate that ANXA2 is important for PTEN regulation within the PI3K/AKT signaling cascade. Furthermore, we also reveal that ANXA2 inversely regulates the expression of the peroxidase, peroxiredoxin 2, in a reactive oxygen species dependent manner.

Original languageEnglish
Article number492
JournalCancers
Volume11
Issue number4
DOIs
Publication statusPublished - 7 Apr 2019

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