15-Keto prostaglandin E2 suppresses STAT3 signaling and inhibits breast cancer cell growth and progression

Eun Ji Lee; Su-Jung Kim; Young-Il Hahn; Hyo-Jin Yoon; Bitnara Han; Kyeojin Kim; Seungbeom Lee; Kwang Pyo Kim; Young Ger Suh; Hye-Kyung Na; Young-Joon Surh

doi:10.1016/j.redox.2019.101175

15-Keto prostaglandin E₂ suppresses STAT3 signaling and inhibits breast cancer cell growth and progression

Redox Biol. 2019 May:23:101175. doi: 10.1016/j.redox.2019.101175. Epub 2019 Mar 28.

Authors

Eun Ji Lee¹, Su-Jung Kim², Young-Il Hahn¹, Hyo-Jin Yoon², Bitnara Han³, Kyeojin Kim⁴, Seungbeom Lee⁵, Kwang Pyo Kim⁶, Young Ger Suh⁷, Hye-Kyung Na⁸, Young-Joon Surh⁹

Affiliations

¹ Department of Molecular Medicine and Biopharmaceutical Science, Seoul National University, Seoul 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
² Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
³ Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, South Korea.
⁴ College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
⁵ College of Pharmacy, CHA University, Gyeonggi-do 11160, South Korea.
⁶ Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, South Korea; Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul 02453, South Korea.
⁷ College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, CHA University, Gyeonggi-do 11160, South Korea.
⁸ Department of Food Science and Biotechnology, Sungshin Women's University, College of Knowledge-Based Services Engineering, Seoul 01133, South Korea. Electronic address: nhk1228@sungshin.ac.kr.
⁹ Department of Molecular Medicine and Biopharmaceutical Science, Seoul National University, Seoul 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul 03080, South Korea. Electronic address: surh@snu.ac.kr.

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.

Keywords: 15-Hydroxyprostaglandin dehydrogenase; 15-Keto-prostaglandin E(2); Breast cancer; MCF10A-ras cells; MDA-MB-231 xenografts; STAT3; Thiol modification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chromatography, Liquid
Dinoprostone / analogs & derivatives*
Dinoprostone / chemistry
Dinoprostone / metabolism
Dinoprostone / pharmacology
Disease Models, Animal
Disease Progression
Female
Humans
Mice
Phosphorylation
Protein Binding
Proteomics / methods
STAT3 Transcription Factor / chemistry
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Signal Transduction* / drug effects
Structure-Activity Relationship
Tandem Mass Spectrometry
Xenograft Model Antitumor Assays

Substances

Biomarkers
STAT3 Transcription Factor
STAT3 protein, human
15-ketoprostaglandin E2
Dinoprostone