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.
Highlights
Lung cancer remains the leading cancer killer around the world [1], especially in China [2], over 85% of lung cancers are diagnosed as non-small cell lung cancer (NSCLC), with 1-year survival rate below 15% [3]
Our results suggest that CS-6 might be a novel inhibitor of heat shock protein 90 (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
After treatment with CS-6 for 36 h, the representative DNA histograms of A549 cells showed that the percentages of G0/G1 phase were decreased from 55.67% to 36.46%, whereas G2/M phase were increased from 16.89% to 34.88%, S phase were not affected by 50 nM CS-6, compared with the control group. These results fully indicated that CS-6 at 10 and 50 nM could both induce G2/M phase arrest of A549 cells
Summary
Lung cancer remains the leading cancer killer around the world [1], especially in China [2], over 85% of lung cancers are diagnosed as non-small cell lung cancer (NSCLC), with 1-year survival rate below 15% [3]. Advanced NSCLC is often treated with radiation therapy or chemotherapy, which could lead many side effects and even increase a person’s risk in developing second cancers later in life. More research is urgently needed to explore new therapy strategies that improve the survival rate, and eliminate suffering of patients with lung cancer. Gamabufotalin (CS-6), a major derivative of bufadienolides, has shown significant antitumor activity, with stable metabolic properties and less adverse effects in previous work [9,10,11], compared with other bufadienolides. As a bioactive molecular, the key signal pathways underlying the anti-cancer mechanism, and the therapeutic targets of CS-6 had not yet been well characterized
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