J Cancer 2018; 9(18):3407-3416. doi:10.7150/jca.24201

Research Paper

Autophagy Inhibition Promotes Bevacizumab-induced Apoptosis and Proliferation Inhibition in Colorectal Cancer Cells

Zhi Zhao1#, Guanggai Xia2#, Ni Li3, Ruping Su1, Xiao Chen1, Li Zhong1✉

1. Department of Gastrointestinal and Hernia Surgery, People's Hospital of Guilin, Guilin, China, 541002
2. Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China, 200233
3. Health Management Center, People's Hospital of Guilin, Guilin, China, 541002
# Zhi Zhao and Guanggai Xia contributed equally to this work.

Abstract

Aim: Anti-VEGF therapy plays an important role in the treatment of malignant tumors, especially metastatic malignant tumors. However, resistance and an inefficient response to anti-VEGF therapy exist. The current study aimed to investigate whether autophagy plays a part in the anti-tumor effect of bevacizumab in colorectal cancer cells.

Methods: VEGF-A expression was measured by immunohistochemical methods. Cell viability and cell apoptosis were detected using 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry. Autophagy was assessed by a western blot, fluorescence microscopy and transmission electron microscopy. HIF-1α was measured using a western blot. A xenograft tumor model of colorectal cancer was constructed to determine the efficacy of the treatment of bevacizumab and chloroquine.

Results: VEGF-A protein was upregulated in colorectal cancer tissue. Anti-VEGF (bevacizumab) inhibited cell viability and induced apoptosis. Moreover, bevacizumab induced autophagy. The inhibition of autophagy by chloroquine or by small interfering RNA promoted bevacizumab-induced apoptosis and proliferation inhibition. Further study showed that bevacizumab treatment significantly augmented HIF-1α. Furthermore, cells pretreated with YC-1, a HIF-1α inhibitor, displayed significantly attenuated bevacizumab-induced autophagy. Finally, a combinatory treatment of bevacizumab and chloroquine synergistically inhibited tumor growth in a xenograft tumor model of colorectal cancer cells.

Conclusions: Our results showed that the inhibition of autophagy promoted the anti-tumor effect of bevacizumab and may offer a promising therapeutic strategy for colorectal cancer.

Keywords: Autophagy, Anti-VEGF, Bevacizumab, Colorectal cancer

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How to cite this article:
Zhao Z, Xia G, Li N, Su R, Chen X, Zhong L. Autophagy Inhibition Promotes Bevacizumab-induced Apoptosis and Proliferation Inhibition in Colorectal Cancer Cells. J Cancer 2018; 9(18):3407-3416. doi:10.7150/jca.24201. Available from http://www.jcancer.org/v09p3407.htm