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Int. J. Mol. Sci. 2017, 18(5), 935; doi:10.3390/ijms18050935

Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER+ Breast Cancer Cells

1
Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea
2
Department of Animal Biotechnology, Chonbuk National University, Jeonju 54896, Korea
3
Department of Immunology, School of Medicine, Konkuk University, Chungju 27478, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Hsueh-Wei Chang
Received: 9 March 2017 / Revised: 25 April 2017 / Accepted: 26 April 2017 / Published: 30 April 2017
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Abstract

Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER+) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the PXN gene promoter. We also investigated the migration and invasive ability of nobiletin in ER+ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER+ breast cancer cells. View Full-Text
Keywords: nobiletin; angiogenesis; FAK; Src; STAT3; PXN nobiletin; angiogenesis; FAK; Src; STAT3; PXN
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Sp, N.; Kang, D.Y.; Joung, Y.H.; Park, J.H.; Kim, W.S.; Lee, H.K.; Song, K.-D.; Park, Y.-M.; Yang, Y.M. Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER+ Breast Cancer Cells. Int. J. Mol. Sci. 2017, 18, 935.

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