1. 15-Keto prostaglandin E2 suppresses STAT3 signaling and inhibits breast cancer cell growth and progression
- Author
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Kyeojin Kim, Kwang Pyo Kim, Eun Lee, Hyo-Jin Yoon, Young-Ger Suh, Su-Jung Kim, Young-Joon Surh, Bitnara Han, Young-Il Hahn, Seungbeom Lee, and Hye-Kyung Na
- Subjects
0301 basic medicine ,Proteomics ,Clinical Biochemistry ,Biochemistry ,Dithiothreitol ,STAT3 ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Breast cancer ,Cell Movement ,Tandem Mass Spectrometry ,Prostaglandin E2 ,Phosphorylation ,lcsh:QH301-705.5 ,lcsh:R5-920 ,biology ,Transfection ,Cell biology ,Disease Progression ,MCF10A-ras cells ,lipids (amino acids, peptides, and proteins) ,Female ,lcsh:Medicine (General) ,medicine.drug ,Protein Binding ,Signal Transduction ,STAT3 Transcription Factor ,Breast Neoplasms ,Dinoprostone ,03 medical and health sciences ,Structure-Activity Relationship ,15-Hydroxyprostaglandin dehydrogenase ,MDA-MB-231 xenografts ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,Organic Chemistry ,Thiol modification ,Lipid signaling ,Novel targets of lipoxidation and potential therapeutic strategy ,Xenograft Model Antitumor Assays ,15-Keto-prostaglandin E2 ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,chemistry ,Apoptosis ,biology.protein ,STAT protein ,030217 neurology & neurosurgery ,Biomarkers ,Chromatography, Liquid - Abstract
Overproduction of prostaglandin E2 (PGE2) has been linked to enhanced tumor cell proliferation, invasiveness and metastasis as well as resistance to apoptosis. 15-Keto prostaglandin E2 (15-keto PGE2), a product formed from 15-hydroxyprostaglandin dehydrogenase-catalyzed oxidation of PGE2, has recently been shown to have anti-inflammatory and anticarcinogenic activities. In this study, we observed that 15-keto PGE2 suppressed the phosphorylation, dimerization and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) in human mammary epithelial cells transfected with H-ras (MCF10A-ras). 15-Keto PGE2 inhibited the migration and clonogenicity of MCF10A-ras cells. In addition, subcutaneous injection of 15-keto PGE2 attenuated xenograft tumor growth and phosphorylation of STAT3 induced by breast cancer MDA-MB-231 cells. However, a non-electrophilic analogue, 13,14-dihydro-15-keto PGE2 failed to inhibit STAT3 signaling and was unable to suppress the growth and transformation of MCF10A-ras cells. These findings suggest that the α,β-unsaturated carbonyl moiety of 15-keto PGE2 is essential for its suppression of STAT3 signaling. We observed that the thiol reducing agent, dithiothreitol abrogated 15-keto PGE2-induced STAT3 inactivation and disrupted the direct interaction between 15-keto PGE2 and STAT3. Furthermore, a molecular docking analysis suggested that Cys251 and Cys259 residues of STAT3 could be preferential binding sites for this lipid mediator. Mass spectral analysis revealed the covalent modification of recombinant STAT3 by 15-keto PGE2 at Cys259. Taken together, thiol modification of STAT3 by 15-keto PGE2 inactivates STAT3 which may account for its suppression of breast cancer cell proliferation and progression., Highlights • 15-Keto-prostaglandin E2 inhibits activation of STAT3 in MCF10A-ras cells. • 15-Keto-prostaglandin E2 suppresses the growth and transformation of MCF10A-ras cells. . • 15-Keto-prostaglandin E2 attenuated xenograft tumor growth and STAT3 phosphorylation. . • 15-Keto PGE2 modulates STAT3 by directly binding to its Cys259 residue.
- Published
- 2019