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

  • Int J Mol Sci. 2017 Apr 30;18(5):935. doi: 10.3390/ijms18050935.
Nipin Sp  1 ,  Dong Young Kang  2 ,  Youn Hee Joung  3 ,  Jong Hwan Park  4 ,  Wan Seop Kim  5 ,  Hak Kyo Lee  6 ,  Ki-Duk Song  7 ,  Yeong-Min Park  8 ,  Young Mok Yang  9
Affiliations
  • 1. Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. [email protected].
  • 2. Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. [email protected].
  • 3. Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. [email protected].
  • 4. Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. [email protected].
  • 5. Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. [email protected].
  • 6. Department of Animal Biotechnology, Chonbuk National University, Jeonju 54896, Korea. [email protected].
  • 7. Department of Animal Biotechnology, Chonbuk National University, Jeonju 54896, Korea. [email protected].
  • 8. Department of Immunology, School of Medicine, Konkuk University, Chungju 27478, Korea. [email protected].
  • 9. Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. [email protected].
PMID: 28468300 DOI: 10.3390/ijms18050935
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.

Keywords
FAK; PXN; STAT3; Src; angiogenesis; nobiletin.
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