Castaldo Stéphanie Anais, Ajime Tom, Serrão Gisela, Anastácio Fábio, Rosa Joana Teixeira, Giacomantonio Carman Anthony, Howarth Alison, Hill Richard, Madureira Patrícia Alexandra
Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Building 8, Room 2.22, 8005-139 Faro, Portugal.
Department of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
Cancers (Basel). 2019 Apr 7;11(4):492. doi: 10.3390/cancers11040492.
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.
过氧化氢（H₂O₂）是致癌信号网络（包括Ras和生长因子受体途径）中的主要第二信使。这主要是通过氧化蛋白质中对氧化还原敏感的半胱氨酸（Cys）残基来实现的，从而导致其结构和功能发生变化。我们之前将膜联蛋白A2（ANXA2）鉴定为一种氧化还原调节蛋白，并发现它在氧化应激过程中发挥重要的细胞作用，同时也促进肿瘤发生。在此，我们研究了ANXA2在驱动肿瘤进展的H₂O₂依赖性信号传导调节中的作用。我们发现，在表皮生长因子（EGF）/表皮生长因子受体（EGFR）刺激或致癌Ras转化后，ANXA2的缺失会导致AKT的激活增强。磷酸酶和张力蛋白同源物（PTEN）蛋白对PI3K/AKT途径起负调节作用。我们证明，ANXA2通过其反应性Cys-8残基与PTEN结合，并且PTEN和ANXA2（而非ANXA2 Cys-8-Ala突变体）的共表达会抑制AKT在丝氨酸473处的磷酸化。这些结果表明，ANXA2在PI3K/AKT信号级联反应中对PTEN的调节很重要。此外，我们还发现ANXA2以依赖活性氧的方式反向调节过氧化物酶——过氧化物还原酶2的表达。
