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VEGFR2 inhibition hampers breast cancer cell proliferation via enhanced mitochondrial biogenesis

Cancer Biology & Medicine 2021年第1期18卷 139-154页

作者： Hao Ni Min Guo Xuepei Zhang Lei Jiang Shuai Tan Juan Yuan Huanhuan L Cui Yanan Min Junhao Zhang Susanne Schlisio Chunhong Ma Wangjun Liao monica nister Chunlin Chen Shuijie Li Nailin Li Department of Gynaecology and Obstetrics Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Karolinska Institutet Department of Medicine-SolnaClinical Pharmacology GroupKarolinska University Hospital-SolnaStockholm 17176Sweden Karolinska Institutet Department of Oncology-PathologyBio ClinicumSolna 17164Sweden State Key Laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China Department of Pathology Zhejiang Provincial Key Laboratory of PathophysiologyNingbo University School of MedicineNingbo 315211China Department of Hematology Affiliated Hospital of Jining Medical UniversityJining 272000China Department of Cell and Molecular Biology Stockholm 17177Sweden Karolinska Institutet Department of MicrobiologyTumor and Cell BiologyStockholm 17177Sweden Shandong University Cheeloo Medical College School of Basic MedicineDepartment of ImmunologyJinan 250000China Department of Oncology Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China

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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