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SHIP2 inhibition alters redox-induced PI3K/AKT and MAP kinase pathways via PTEN over-activation in cervical cancer cells.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-09-02 , DOI: 10.1002/2211-5463.12967
Abdelhalim Azzi 1
Affiliation  

Phosphatidylinositol (3,4,5)‐trisphosphate (PI(3,4,5)P3) is required for protein kinase B (AKT) activation. The level of PI(3,4,5)P3 is constantly regulated through balanced synthesis by phosphoinositide 3‐kinase (PI3K) and degradation by phosphoinositide phosphatases phosphatase and tensin homologue (PTEN) and SH2‐domain containing phosphatidylinositol‐3,4,5‐trisphosphate 5‐phosphatase 2 (SHIP2), known as negative regulators of AKT. Here, I show that SHIP2 inhibition in cervical cancer cell lines alters H2O2‐mediated AKT and mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathway activation. In addition, SHIP2 inhibition enhances reactive oxygen species generation. Interestingly, I found that SHIP2 inhibition and H2O2 treatment enhance lipid and protein phosphatase activity of PTEN. Pharmacological targeting or RNA interference(RNAi) mediated knockdown of PTEN rescues extracellular signal‐regulated kinase and AKT activation. Using a series of pharmacological and biochemical approaches, I provide evidence that crosstalk between SHIP2 and PTEN occurs upon an increase in oxidative stress to modulate the activity of mitogen‐activated protein kinase and phosphoinositide 3/ATK pathways.

中文翻译:

SHIP2 抑制通过宫颈癌细胞中的 PTEN 过度激活来改变氧化还原诱导的 PI3K/AKT 和 MAP 激酶通路。

蛋白激酶 B (AKT) 激活需要磷脂酰肌醇 (3,4,5)-三磷酸 (PI(3,4,5)P3)。PI(3,4,5)P3 的水平通过磷酸肌醇 3-激酶 (PI3K) 的平衡合成和磷酸肌醇磷酸酶磷酸酶和张力蛋白同源物 (PTEN) 和含有磷脂酰肌醇-3,4,5 的 SH2 结构域的降解不断调节-三磷酸 5-磷酸酶 2 (SHIP2),被称为 AKT 的负调节剂。在这里,我展示了宫颈癌细胞系中的 SHIP2 抑制改变了 H 2 O 2介导的 AKT 和丝裂原活化蛋白激酶/细胞外信号调节激酶通路的激活。此外,SHIP2 抑制增强了活性氧的生成。有趣的是,我发现 SHIP2 抑制和 H 2 O 2处理增强 PTEN 的脂质和蛋白磷酸酶活性。药理学靶向或 RNA 干扰 (RNAi) 介导的 PTEN 敲低可挽救细胞外信号调节激酶和 AKT 激活。使用一系列药理学和生化方法,我提供证据表明 SHIP2 和 PTEN 之间的串扰发生在氧化应激增加以调节丝裂原活化蛋白激酶和磷酸肌醇 3/ATK 途径的活性时。
更新日期:2020-10-02
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