Annexin A2 Regulates AKT Upon H₂O₂-Dependent Signaling Activation in Cancer Cells

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Annexin A2 Regulates AKT Upon H₂O₂-Dependent Signaling Activation in Cancer Cells

Tuesday, 23.04.2019

 

Authors and Affiliations:

Castaldo SA1, , Ajime T1, Serrão G1, Anastácio F1, Rosa JT1, Giacomantonio CA2, Howarth A3, Hill R1,3, and Madureira PA1, 3

1 Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal;

2 Department of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada;

3 Brain Tumour Research Centre of Excellence, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, UK;

Current Address: VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, 3000 Leuven, Belgium.

 

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.

 

Journal: Cancers

 

Link: https://www.mdpi.com/2072-6694/11/4/492

 

Funding: P.A.M. é financiada por um contrato Investigador FCT da Fundação para a Ciência e a Tecnologia (FCT), Portugal, ref:IF/00614/2014, e um projeto exploratório da FCT, ref:IF/00614/2014/CP12340006. O Centro de Investigação em Biomedicina (Centre for Biomedical Research, CBMR) da Universidade do Algarve é financiado pela FCT, ref:UID/BIM/04773/2013CBMR1334. S.A.C. foi financiada por uma bolsa de investigação da FCT, ref: WELCOMEII/57/UALG/1050/2011. T.A. foi recipiente de uma bolsa ERASMUS Mundus (EMQAL), ref: FPAnr2013-0225. A.H. foi financiada por uma bolsa de doutoramento da Fundação Ollie Young, ref: 1148511. R.H. é financiado pela Fundação Brain Tumour Research.