15-Deoxy-Δ12,14-prostaglandin J2 activates PI3K-Akt signaling in human breast cancer cells through covalent modification of the tumor suppressor PTEN at cysteine 136.

摘要: Abstract 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products cyclooxygenase-2-catalized arachidonic acid metabolism, has been shown to stimulate breast cancer cell proliferation and migration through Akt activation, but underlying mechanisms remain poorly understood. In present study, we investigated effects 15d-PGJ2 on activity PTEN, inhibitor phosphoinositide 3-kinase (PI3K)-Akt axis, in human (MCF-7) cells. Since α,β-unsaturated carbonyl moiety cyclopentenone ring is electrophilic, hypothesized that 15d-PGJ2-induced phosphorylation might result from covalent modification subsequent inactivation PTEN several critical cysteine residues. When treated MCF-7 cells, bound this was abolished presence thiol-reducing agent dithiothreitol. A mass spectrometric analysis by using recombinant endogenous protein revealed 136 residue (Cys136) covalently modified upon treatment with 15d-PGJ2. Notably, ability bind as well induce cells expressing a mutant form which Cys136 replaced serine (C136S-PTEN). The study demonstrates for first time electrophilic directly binds provides new insight into loss progression associated chronic inflammation. These observations suggest can undergo nucleophilic addition presumably at Cys136, thereby inactivating tumor suppressor concomitant activation.