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
Affiliations
Eun Ji Lee
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
Su-Jung Kim
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
Young-Il Hahn
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
Hyo-Jin Yoon
Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
Bitnara Han
Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, South Korea
Kyeojin Kim
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
Seungbeom Lee
College of Pharmacy, CHA University, Gyeonggi-do 11160, South Korea
Kwang Pyo Kim
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
Young Ger Suh
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, CHA University, Gyeonggi-do 11160, South Korea
Hye-Kyung Na
Department of Food Science and Biotechnology, Sungshin Women's University, College of Knowledge-Based Services Engineering, Seoul 01133, South Korea; Corresponding author. Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, 55 Dobong-ro 76 ga-gil, Gangbuk-gu, Seoul 01133, South Korea.
Young-Joon Surh
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; Corresponding author. College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea.
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: Breast cancer, 15-Hydroxyprostaglandin dehydrogenase, 15-Keto-prostaglandin E2, STAT3, Thiol modification, MCF10A-ras cells, MDA-MB-231 xenografts