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

被引:32
|
作者
Castaldo, Stephanie Anais [1 ,4 ,5 ]
Ajime, Tom [1 ]
Serrao, Gisela [1 ]
Anastacio, Fabio [1 ]
Rosa, Joana Teixeira [1 ]
Giacomantonio, Carman Anthony [2 ]
Howarth, Alison [3 ]
Hill, Richard [1 ,3 ]
Madureira, Patricia Alexandra [1 ,3 ]
机构
[1] Univ Algarve, Ctr Biomed Res CBMR, Bldg 8,Room 2-22, P-8005139 Faro, Portugal
[2] Dalhousie Univ, Dept Med, Halifax, NS B3H 4R2, Canada
[3] Univ Portsmouth, Brain Tumour Res Ctr Excellence, Inst Biomed & Biomol Sci, Portsmouth PO1 2DT, Hants, England
[4] Univ Leuven, VIB Ctr Canc Biol, B-3000 Leuven, Belgium
[5] Univ Leuven, KU Leuven, Dept Oncol, B-3000 Leuven, Belgium
来源
CANCERS | 2019年 / 11卷 / 04期
关键词
ANXA2; PTEN; PI3K/AKT; PRDX2; H2O2-dependent signaling; REDOX REGULATION; PROTEIN; RAS; TRANSPORT;
D O I
10.3390/cancers11040492
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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收藏
页数:15
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