Oncotarget

Research Papers:

Quantitative proteomics reveals molecular mechanism of gamabufotalin and its potential inhibition on Hsp90 in lung cancer

Liyuan Zhang, Zhenlong Yu, Yan Wang, Xiaobo Wang, Lianru Zhang, Chao Wang, Qingxi Yue, Xun Wang, Sa Deng, Xiaokui Huo, Xiangge Tian, Shanshan Huang, Baojing Zhang and Xiaochi Ma _

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Oncotarget. 2016; 7:76551-76564. https://doi.org/10.18632/oncotarget.10388

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Abstract

Liyuan Zhang1,*, Zhenlong Yu1,2,*, Yan Wang1,2, Xiaobo Wang2, Lianru Zhang3, Chao Wang1, Qingxi Yue1,4, Xun Wang5, Sa Deng1, Xiaokui Huo1, Xiangge Tian1, Shanshan Huang1, Baojing Zhang1, Xiaochi Ma1

1Dalian Medical University, Dalian, China

2Department of Pharmacy and Traditional Chinese Medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China

3State Key Lab of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China

4Institute of Oncology, Shanghai 9th People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

5Department of Nuerosurgery, The Third People's Hospital of Dalian, Non-Directly Affiliated Hospital of Dalian Medical University, Dalian, China

*These authors contributed equally to this work

Correspondence to:

Xiaobo Wang, email: [email protected]

Qingxi Yue, email: [email protected]

Xiaochi Ma, email: [email protected]

Keywords: gamabufotalin, heat shock protein 90 (Hsp90), quantitative proteomics, gene ontology (GO), NSCLC

Received: March 10, 2016     Accepted: May 05, 2016     Published: July 02, 2016

ABSTRACT

Gamabufotalin (CS-6) is a major bufadienolide of Chansu, which shows desirable metabolic stability and less adverse effect in cancer therapy. CS-6 treatment inhibited the proliferation of NSCLC in a nanomolar range. And CS-6 could induce G2/M cell cycle arrest and apoptosis in A549 cells. However, its molecular mechanism in antitumor activity remains poorly understood. We employed a quantitative proteomics approach to identify the potential cellular targets of CS-6, and found 38 possible target-related proteins. Among them, 31 proteins were closely related in the protein-protein interaction network. One of the regulatory nodes in key pathways was occupied by Hsp90. Molecular docking revealed that CS-6 interacted with the ATP-binding sites of Hsp90. In addition, CS-6 inhibited the chaperone function of Hsp90 and reduced expression of Hsp90-dependent client proteins. Moreover, CS-6 markedly down-regulated the protein level of Hsp90 in tumor tissues of the xenograft mice. Taken together, our results suggest that CS-6 might be a novel inhibitor of Hsp90, and the possible network associated with CS-6 target-related proteins was constructed, which provided experimental evidence for the preclinical value of using CS-6 as an effective antitumor agent in treatment of NSCLC.


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