title: Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer.
abstract: Mouse double minute 2 (MDM2) and vascular endothelial growth factor (VEGF) are important molecules involved in tumor progression. We researched potential inhibitors that simultaneously target MDM2 and VEGF. In our recent study involving the performance of high-throughput screening with a fluorescence polarization assay, gossypol was identified as one of the top hits that inhibit protein-RNA binding activity. Because MDM2 is an RNA-binding protein and its targets include VEGF mRNA, we investigated whether gossypol has an inhibitory effect on MDM2-VEGF.
  
  
  
  UV cross-linking and RNA binding assay, isothermal titration calorimetry assay, and ubiquitination assay were performed to determine mechanisms by which gossypol functions as a dual inhibitor of MDM2 and VEGF. The effect of gossypol on MDM2 and VEGF expression, cancer cell apoptosis, tumor growth and VEGF-mediated angiogenesis were studied in vitro and in vivo in different human breast cancer models with a different p53 status.
  
  
  
  We observed that gossypol inhibited expression of both MDM2 and VEGF in human breast cancer cells with either wild-type or mutant p53. A nechanistic study further demonstrated that, through disrupting the interaction between MDM2 protein and VEGF mRNA, gossypol induced MDM2 self-ubiquitination and decreased VEGF translation simultaneously, which resulted in both apoptosis and anti-angiogenesis effects. In vitro, regardless of p53 status, gossypol induced cancer cell apoptosis. In nude mouse xenograft in vivo models, gossypol suppressed tumor growth and VEGF-mediated angiogenesis.
  
  
  
  Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer. Our study reveals a novel mechanism by which gossypol functions as an anticancer agent. We believe that MDM2-VEGF targeting represents a novel strategy for improving cancer outcome.
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Department of Pathology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jiansha
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. sutiefen@hotmail.com.|Department of Pathology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, 430030, China. sutiefen@hotmail.com.
authors.forename: Tiefen
authors.initials: T
authors.lastname: Su
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. zhou71@163.com.
authors.forename: Sheng
authors.identifier: 0000-0001-7369-2413
authors.initials: S
authors.lastname: Zhou
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006072:Gossypol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; D042442:Vascular Endothelial Growth Factors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D006072:Gossypol
keywords: Breast neoplasms; Gossypol; MDM2; VEGF