15-Keto Prostaglandin E2 Inhibits Proliferation of Breast Cancer Cells through Suppression of STAT3 Signaling

15-Keto PGE2;electrophile;α;β-unsaturated carbonyl group;STAT3;thiol modification;MCF10A-ras;MDA-MB-231 xenografts;610

융합과학기술대학원 분자의학 및 바이오제약학과 ;

University:서울대학교 대학원

关键词: 15-Keto PGE2;    electrophile;    α;    β-unsaturated carbonyl group;    STAT3;    thiol modification;    MCF10A-ras;    MDA-MB-231 xenografts;    610;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/133423/1/000000141946.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Prostaglandin E2 (PGE2) is highly produced during inflammation and cancer. Overproduction of PGE2 has been associated with increased tumor cell proliferation, resistance to apoptosis and invasiveness. PGE2 is oxidized to 15-keto prostaglandin E2 (15-keto PGE2) by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-Keto PGE2 is considered as a biologically inactive form of the pro-tumorigenic lipid mediator, PGE2. However, recent studies have revealed that 15-keto PGE2 has tumor suppressive functions, but the underlying molecular mechanisms remain to be elucidated. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates transcription of genes involved in cell proliferation, cell cycle progression and cell survival. It is constitutively activated in most of cancer types, and the aberrantly activated STAT3 contributes to tumor promotion and progression. This prompted me to investigate the effects of 15-keto PGE2 on STAT3 activation. Notably, 15-keto PGE2 containing an α,β-unsaturated carbonyl group directly bound to STAT3 and thereby suppressed the phosphorylation, dimerization and nuclear translocation of this transcription factor in Ha-Ras transformed human mammary epithelial (MCF10A-ras) cells. In contrast, its non-electrophilic analogue, 13,14-dihydro-15-keto PGE2 failed to inhibit the STAT3 activation and was unable to suppress the growth and transformation of MCF10A-ras cells. Moreover, thiol reducing agents, such as dithiothreitol or N-acetyl-L-cysteine, disrupted the interaction between 15-keto PGE2 and STAT3, and abrogated STAT3 inactivation by 15-keto PGE2. A molecular docking analysis suggests that Cys251 and Cys259 residues of STAT3 are preferential binding sites for this lipid mediator. In addition, subcutaneous injection of 15-keto PGE2 attenuated xenograft tumor growth and decreased phosphorylated STAT3 in athymic nude mice transplanted with human breast cancer MDA-MB-231 cells. Taken together, thiol modification of STAT3 by 15-keto PGE2 inhibits STAT3 activation, thereby suppressing breast cancer cell proliferation, growth and transformation.