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VEGFR2 inhibition hampers breast cancer cell proliferation via enhanced mitochondrial biogenesis

查看全文 作　　者：Hao [1,2]Ni;Min [3]Guo;Xuepei [4]Zhang;Lei [2,5]Jiang;Shuai [2]Tan;Juan [7]Yuan;Huanhuan L [3]Cui;Yanan [2,6]Min;Junhao [10]Zhang;Susanne [8]Schlisio;Chunhong [9]Ma;Wangjun [10]Liao;Monica [3]Nister;Chunlin [1]Chen;Shuijie [9]Li;Nailin [2]Li 高影响力作者 机构地区：[1]Department of Gynaecology and Obstetrics,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;[2]Karolinska Institutet,Department of Medicine-Solna,Clinical Pharmacology Group,Karolinska University Hospital-Solna,Stockholm 17176,Sweden;[3]Karolinska Institutet,Department of Oncology-Pathology,Bio Clinicum,Solna 17164,Sweden;[4]State Key Laboratory of Bioorganic and Natural Products Chemistry,Center for Excellence in Molecular Synthesis,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China;[5]Department of Pathology,Zhejiang Provincial Key Laboratory of Pathophysiology,Ningbo University School of Medicine,Ningbo 315211,China;[6]Department of Hematology,Affiliated Hospital of Jining Medical University,Jining 272000,China;[7]Department of Cell and Molecular Biology,Stockholm 17177,Sweden;[8]Karolinska Institutet,Department of Microbiology,Tumor and Cell Biology,Stockholm 17177,Sweden;[9]Shandong University Cheeloo Medical College,School of Basic Medicine,Department of Immunology,Jinan 250000,China;[10]Department of Oncology,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China高影响力机构 出　　处：《Cancer Biology & Medicine》索引2021年第18卷第1期,共16页高影响力期刊 基　　金：supported by grants from the Swedish HeartLung Foundation(Grant No.20160419);the Swedish Research Council;the Swedish Foundation for International Cooperation in Research and Higher Education;the National Natural Science Foundation of China(Grant Nos.81700110 and 8171101454);the China Scholarship Council;Karolinska Institutet;Shandong University-Karolinska Institutet Cooperative Research Fund;the Stockholm County Council。 摘　　要：Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain elusive.The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation.Methods:VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor,Ki8751,and the breast cancer cell lines,MCF-7 and MDA-MB-231,using flow cytometry,mass spectrometry,immunoblotting,and confocal microscopy.Data were analyzed using one-way analysis of variance followed by Tukey’s multiple comparison test.Results:VEGF blockade by Ki8751 significantly reduced cancer cell proliferation,and enhanced breast cancer cell apoptosis.Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins,suggesting the involvement of mitochondrial biogenesis.Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells,induced endomitosis,and arrested cancer cells in the high aneuploid phase.VEGFR2 knockdown by sh RNAs showed similar effects to those of Ki8751,confirming the specificity of Ki8751 treatment.Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species(ROS)production,which induced cancer cell apoptosis.Furthermore,Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α,and translocated PGC1αinto the nucleus.The PGC1αalterations increased mitochondrial transcription factor A(TFAM)expression and subsequently increased mitochondrial biogenesis.Conclusions:VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis,ROS production,and cell apoptosis.These findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production. 关 键 词：Breast cancer VEGF VEGFR2 MITOCHONDRIA TFAM ROS apoptosis
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