In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2594-2594
Abstract:
Our previous studies demonstrated that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor γ, inhibited cell proliferation and induces apoptosis in several cancerous and transformed cell lines. 15d-PGJ2 contains α,β-unsaturated carbonyl groups that can form reversible adducts with thiol nucleophiles. In the present work, we synthesized a series of 15d-PGJ2 analogues by saturating an electrophilic α,β-unsaturated carbonyl moiety in the cyclopentenone ring. Among these, 14,15-dihydro-PGJ2 with a more electrophilic carbon exhibited a potent growth inhibitory activity and induced apoptosis to a greater extent than did 15d-PGJ2. 14,15-Dihydro-PGJ2 as well as 15d-PGJ2 inhibited activation of STAT3, which appeared to be associated with their direct binding to this transcription factor. In contrast, both 9,10-dihydro-15d-PGJ2 and 12,13-14,15-tetrahydro-PGJ2 failed to induce apoptosis and STAT3 activation due to lack of the electrophilic α,β-unsaturated carbonyl moiety. Molecular docking studies suggested that the electrophilic carbon atom of 14,15-dihydro-PGJ2 is placed well in the vicinity of Cys259 of STAT3 to form a covalent Michael adduct. Site-directed mutation of Cys259 of STAT3 abolished its interaction with 15d-PGJ2. 14,15-dihydro-PGJ2 can stably interacted with STAT3, this synthetic cyclopentenone analogue can hence be utilized as a lead compound to develop STAT3 specific inhibitors with anti-tumorigenic activity. Citation Format: Su-Jung Kim, Young-Il Hahn, Bu Young Choi, Young-Ger Suh, Hye-Kyung Na, Young-Joon Surh. 15-Deoxy-Δ12,14-prostaglandin J2 induces apoptosis through covalent interaction with STAT3: structure-activity relationship and underlying molecular mechanisms. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washi ngton, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2594. doi:10.1158/1538-7445.AM2013-2594
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-2594
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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