Therapeutic Potential of Apatinib Against Colorectal Cancer by Inhibiting VEGFR2-Mediated Angiogenesis and β-Catenin Signaling

Xiaomin Cai; Bin Wei; Lele Li; Xiaofeng Chen; Jing Yang; Xiaofei Li; Xiaozheng Jiang; Mu Lv; Mingyang Li; Yumeng Lin; Qiang Xu; Wenjie Guo; Yanhong Gu

doi:10.2147/OTT.S266549

Therapeutic Potential of Apatinib Against Colorectal Cancer by Inhibiting VEGFR2-Mediated Angiogenesis and β-Catenin Signaling

Onco Targets Ther. 2020 Oct 29:13:11031-11044. doi: 10.2147/OTT.S266549. eCollection 2020.

Authors

Xiaomin Cai^#¹, Bin Wei^#^{1

2}, Lele Li^#¹, Xiaofeng Chen¹, Jing Yang¹, Xiaofei Li¹, Xiaozheng Jiang¹, Mu Lv¹, Mingyang Li¹, Yumeng Lin³, Qiang Xu³, Wenjie Guo³, Yanhong Gu¹

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
² Department of Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an 223300, People's Republic of China.
³ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Apatinib is an inhibitor of VEGFR2 (vascular endothelial growth factor receptor 2) that has attracted a great deal of attention due to its promotion of anticancer activity. In the present study, we investigated the therapeutic effects of apatinib against colorectal cancer (CRC) and examined the underlying mechanism.

Materials and methods: Both in vivo and in vitro assays were conducted to study the effect of apatinib on CRC. To elucidate the associated mechanism, RNA-seq (transcriptome) analysis was conducted on apatinib-treated HCT116 cells.

Results: Apatinib showed antiproliferative and proapoptotic effects, induced G0/G1 arrest and blocked cell migration and invasion in CRC. An analysis of the mechanism associated with apatinib activity demonstrated that by interacting with VEGFR2, apatinib decreased p-Src, p-Akt, and p-GSK3β levels, which further increased β-catenin ubiquitination and reduced the nuclear translocation of β-catenin. Furthermore, apatinib strongly suppressed CT26 cell growth in mouse xenograft models by inhibiting β-catenin signaling and angiogenesis.

Conclusion: Overall, the results of the present study here indicated that by inhibiting the VEGFR2-β-catenin-mediated malignant phenotype, apatinib significantly suppresses the growth of CRC, suggesting that the use of apatinib is a promising therapeutic strategy for CRC.

Keywords: VEGFR2; angiogenesis; apatinib; colorectal cancer; β-catenin.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Nos. 81871944, 81572389), Jiangsu province key medical talents (ZDRCA2016026) and Priority Academic Program Development of Jiangsu Higher Education Institutions. Project was supported by the National Training Program for Innovation and Entrepreneurship for undergraduate students (G201810284152), Jiangsu Students’ Platform for innovation and entrepreneurship training program (201710312008Z), Fundamental Research Funds for the Central Universities (020814380114).