alkylation of the tumor suppressor pten activates akt and β-catenin signaling a mechanism linking inflammation and oxidative stress with cancer烷基化的肿瘤抑制基因pten akt和β-catenin信号连接与癌症炎症和氧化应激机制.pdfVIP

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alkylation of the tumor suppressor pten activates akt and β-catenin signaling a mechanism linking inflammation and oxidative stress with cancer烷基化的肿瘤抑制基因pten akt和β-catenin信号连接与癌症炎症和氧化应激机制.pdf

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alkylation of the tumor suppressor pten activates akt and β-catenin signaling a mechanism linking inflammation and oxidative stress with cancer烷基化的肿瘤抑制基因pten akt和β-catenin信号连接与癌症炎症和氧化应激机制

Alkylation of the Tumor Suppressor PTEN Activates Akt and b-Catenin Signaling: A Mechanism Linking Inflammation and Oxidative Stress with Cancer Tracy M. Covey¤a, Kornelia Edes, Gary S. Coombs¤a, David M. Virshup¤a, Frank A. Fitzpatrick*¤b Department of Medicinal Chemistry, University of Utah Health Sciences Center, Salt Lake City, Utah, United States of America Abstract 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 a,b-enals (acrolein, 4-hydroxy-2-nonenal) and a,b- enones (prostaglandin A , D12-prostaglandin J and 15-deoxy-D-12,14-prostaglandin J ) covalently modify and inactivate 2 2 2 cellular PTEN, with ensuing activation of PKB/Akt kinase; phosphorylation of Akt substrates; increased cell proliferation; and increased nuclear b-catenin signaling. Alkylation of PTEN by a,b-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. Citation: Covey TM, Edes K, Coombs GS, Virshup DM, Fitzpatrick FA (2010) Alkylation of the Tumor Suppressor PTEN Activates Akt and b-Catenin Signaling: A Mechanism Linking Inflammation and Oxidative Stress with Cancer. PLoS ONE 5(10): e13545. doi:10.1371/journal.pone.001