Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.
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.
Covey
Tracy M
TM
Department of Medicinal Chemistry, University of Utah Health Sciences Center, Salt Lake City, Utah, United States of America.
Edes
Kornelia
K
Coombs
Gary S
GS
Virshup
David M
DM
Fitzpatrick
Frank A
FA
D000478:Alkylation; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human