Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.
Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.
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DOI：
10.1371/journal.pone.0013545
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发表时间：
2010-10-21
期刊：
影响因子：
3.7
通讯作者：
Fitzpatrick FA
中科院分区：
文献类型：
--
作者：
Covey TM;Edes K;Coombs GS;Virshup DM;Fitzpatrick FA
PTEN是一种磷酸肌醇-3-磷酸酶，具有肿瘤抑制和细胞合成代谢/分解代谢调节的双重作用。PTEN中氧化还原敏感的半胱氨酰硫醇通过过氧化氢进行信号转导的适应可能叠加了对氧化应激和炎症的其他介质的脆弱性，特别是反应性羰基物质，其是花生四烯酸过氧化的常见副产物。利用MCF 7和HEK-293细胞，我们报道了几种反应性醛和酮，例如亲电子的α，β-烯醛，（丙烯醛，4-羟基-2-壬烯醛）和α，β-烯酮（前列腺素A2、Δ12-前列腺素J2和15-脱氧-Δ-12，14-前列腺素J2）共价修饰和修饰细胞PTEN，随后激活PKB/Akt激酶; Akt底物磷酸化;增加的细胞增殖;和增加的核β-连环蛋白信号传导。α，β-烯醛/烯酮对PTEN的烷基化及其对细胞PKB/Akt信号传导抑制的干扰可能加重与慢性炎症、氧化应激或衰老相关的增生性和肿瘤性疾病。
PTEN, a phosphoinositide-3-phosphatase, serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism. Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimposed a vulnerability to other mediators of oxidative stress and inflammation, especially reactive carbonyl species, which are commonly occurring by-products of arachidonic acid peroxidation. Using MCF7 and HEK-293 cells, we report that several reactive aldehydes and ketones, e.g. electrophilic α,β-enals (acrolein, 4-hydroxy-2-nonenal) and α,β-enones (prostaglandin A2, Δ12-prostaglandin J2 and 15-deoxy-Δ-12,14-prostaglandin J2) covalently modify and inactivate cellular PTEN, with ensuing activation of PKB/Akt kinase; phosphorylation of Akt substrates; increased cell proliferation; and increased nuclear β-catenin signaling. Alkylation of PTEN by α,β-enals/enones and interference with its restraint of cellular PKB/Akt signaling may accentuate hyperplastic and neoplastic disorders associated with chronic inflammation, oxidative stress, or aging.
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