Oncotarget

Research Papers:

Pazopanib, a novel multi-kinase inhibitor, shows potent antitumor activity in colon cancer through PUMA-mediated apoptosis

Lingling Zhang _, Huanan Wang, Wei Li, Juchang Zhong, Rongcheng Yu, Xinfeng Huang, Honghui Wang, Zhikai Tan, Jiangang Wang and Yingjie Zhang

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Oncotarget. 2017; 8:3289-3303. https://doi.org/10.18632/oncotarget.13753

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Abstract

Lingling Zhang1,2,3,4, Huanan Wang1,5, Wei Li2,6, Juchang Zhong1, Rongcheng Yu1, Xinfeng Huang1, Honghui Wang1, Zhikai Tan1, Jiangang Wang3, Yingjie Zhang1,7

1College of Biology, Hunan University, Changsha, China

2Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China

3Department of Internal Medicine, The Third Xiangya Hospital, Central South University, Changsha, China

4School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

5Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China

6Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China

7Shenzhen Institute, Hunan University, Shenzhen, China

Correspondence to:

Yingjie Zhang, email: [email protected]

Jiangang Wang, email: [email protected]

Keywords: colon cancer, PUMA, apoptosis, Akt, p53

Abbreviations: PUMA, p53 up-regulated modulator of apoptosis; Bax, Bcl-2-associated X protein; CCK-8, Cell Counting Kit-8; CRC, colorectal cancer

Received: February 20, 2016     Accepted: October 19, 2016     Published: December 01, 2016

ABSTRACT

Colon cancer is still the third most common cancer which has a high mortality but low five-year survival rate. Novel tyrosine kinase inhibitors (TKI) such as pazopanib become effective antineoplastic agents that show promising clinical activity in a variety of carcinoma, including colon cancer. However, the precise underlying mechanism against tumor is unclear. Here, we demonstrated that pazopanib promoted colon cancer cell apoptosis through inducing PUMA expression. Pazopanib induced p53-independent PUMA activation by inhibiting PI3K/Akt signaling pathway, thereby activating Foxo3a, which subsequently bound to the promoter of PUMA to activate its transcription. After induction, PUMA activated Bax and triggered the intrinsic mitochondrial apoptosis pathway. Furthermore, administration of pazopanib highly suppressed tumor growth in a xenograft model. PUMA deletion in cells and tumors led to resistance of pazopanib, indicating PUMA-mediated pro-apoptotic and anti-tumor effects in vitro and in vivo. Combing pazopanib with some conventional or novel drugs, produced heightened and synergistic antitumor effects that were associated with potentiated PUMA induction via different pathways. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of pazopanib in colon cancer cells and provide the rationale for clinical evaluation.


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