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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer

Authors: Jing Xiong, Jiansha Li, Qin Yang, Jun Wang, Tiefen Su, Sheng Zhou

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.
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Metadata
Title
Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer
Authors
Jing Xiong
Jiansha Li
Qin Yang
Jun Wang
Tiefen Su
Sheng Zhou
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0818-5

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