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15-Keto Prostaglandin E2 Inhibits Proliferation of Breast Cancer Cells through Suppression of STAT3 Signaling
STAT3 억제를 통한 15-Keto prostaglandin E2의 인체 유방암세포 증식 억제 연구

DC Field Value Language
dc.contributor.advisor서영준-
dc.contributor.author이은지-
dc.date.accessioned2017-07-19T11:10:25Z-
dc.date.available2018-03-30-
dc.date.issued2017-02-
dc.identifier.other000000141946-
dc.identifier.urihttps://hdl.handle.net/10371/133423-
dc.description학위논문 (석사)-- 서울대학교 대학원 : 바이오제약학과, 2017. 2. 서영준.-
dc.description.abstractProstaglandin 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.-
dc.description.tableofcontentsⅰ. Introduction 1

ⅱ. Material and Methods 4

ⅲ. Results 13

ⅳ. Discussion 36

ⅴ. References 39

ⅵ. Abstract in Korean 44
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dc.formatapplication/pdf-
dc.format.extent2897946 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subject15-Keto PGE2-
dc.subjectelectrophile-
dc.subjectα-
dc.subjectβ-unsaturated carbonyl group-
dc.subjectSTAT3-
dc.subjectthiol modification-
dc.subjectMCF10A-ras-
dc.subjectMDA-MB-231 xenografts-
dc.subject.ddc610-
dc.title15-Keto Prostaglandin E2 Inhibits Proliferation of Breast Cancer Cells through Suppression of STAT3 Signaling-
dc.title.alternativeSTAT3 억제를 통한 15-Keto prostaglandin E2의 인체 유방암세포 증식 억제 연구-
dc.typeThesis-
dc.description.degreeMaster-
dc.citation.pages45-
dc.contributor.affiliation융합과학기술대학원 분자의학 및 바이오제약학과-
dc.date.awarded2017-02-
Appears in Collections:
Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Theses (Master's Degree_분자의학 및 바이오제약학과)
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