Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.

Published online

Journal Article

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 A(2), Δ12-prostaglandin J(2) and 15-deoxy-Δ-12,14-prostaglandin J(2)) 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.

Full Text

Duke Authors

Cited Authors

  • Covey, TM; Edes, K; Coombs, GS; Virshup, DM; Fitzpatrick, FA

Published Date

  • October 21, 2010

Published In

Volume / Issue

  • 5 / 10

Start / End Page

  • e13545 -

PubMed ID

  • 20975834

Pubmed Central ID

  • 20975834

Electronic International Standard Serial Number (EISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0013545

Language

  • eng

Conference Location

  • United States