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Cancer Lett. 2018 Jun 28;424:30-45. doi: 10.1016/j.canlet.2018.03.016. Epub 2018 Mar 14.

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.

Author information

1
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea.
2
College of Pharmacy, CHA University, Pocheon-si 11160, Gyeonggi-do, South Korea.
3
Department of Food Science and Biotechnology, College of Knowedge-Based Services Engineering, Sungshin Women's University, Seoul 02844, South Korea.
4
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea.
5
Department of Pharmacy, Kyung Hee University, Seoul 02453, South Korea.
6
Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea. Electronic address: surh@snu.ac.kr.

Abstract

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

KEYWORDS:

15-Deoxy-Δ(12,14)-prostaglandin J(2); Akt; Cyclopentenone prostaglandins; PTEN; Thiol modification

PMID:
29550515
DOI:
10.1016/j.canlet.2018.03.016
[Indexed for MEDLINE]

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