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

Nipin Sp,Dong Kang,Jong Park,Ki-Duk Song,Yeong-Min Park,Youn Joung,Wan Kim,Hak Lee,Young Yang

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.

Highlights

Breast cancer is associated with the second highest mortality rate worldwide [1]
We evaluated the ability of nobiletin to inhibit tumor angiogenesis by regulating Steroid receptor coactivator (Src)/focal adhesion kinase (FAK)/Signal transducer and activator of transcription 3 (STAT3) signaling through PXN in Estrogen receptor (ER)+ breast cancer cells
The ER+ cell lines MCF-7 and T47D, the triple-negative breast cancer cell lines MDA-MB-231, Her2+, and SKBR3, and the endothelial cell line human umbilical vein endothelial cells (HUVEC) were treated with various concentrations of nobiletin, and cell proliferation was assessed by comparison with non-treated control cells (Figure 1A)

Summary

Introduction

Breast cancer is associated with the second highest mortality rate worldwide [1]. Among the many causes of breast cancer, environmental factors play an important role [2]. Different factors regulate tumor progression, such as uncontrolled cell proliferation, induction of the cell cycle, and loss of apoptosis-inducing ability. Estrogen receptor (ER) has a significant role in breast cancer and is considered a predictive marker for endocrine therapy in breast cancer patients [3]. Tumor angiogenesis is considered a key hallmark of tumor progression. Formation of new blood vessels occurs as compensation for a lack of blood supply to provide sufficient oxygen for tumor development [4]. Tumors trigger blood vessel formation by secreting several growth factors that can induce capillary growth. Vascular endothelial growth factor (VEGF) is the major growth factor in tumor angiogenesis, and basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) interact with VEGF during this process [5]

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