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