Arsenic trioxide targets Hsp60, triggering degradation of p53 and survivin
Xuqiao Hu, Hongyan Li, Tiffany Ka-Yan Ip, Hilaire Yam Fung Cheung, Mohamad Koohi‐Moghadam, Haibo Wang, Xinming Yang, Daniel N. Tritton, Yuchuan Wang, Yi Wang, Runming Wang, Kwan‐Ming Ng, Hua Naranmandura, Eric Tse, Hongzhe Sun
Abstract
) with quantitative proteomics, allowing 37 arsenic binding and 250 arsenic regulated proteins to be identified in NB4, a human APL cell line. Bioinformatics analysis reveals that ATO disrupts multiple physiological processes, in particular, chaperone-related protein folding and cellular response to stress. Furthermore, we discover heat shock protein 60 (Hsp60) as a vital target of ATO. Through biophysical and cell-based assays, we demonstrate that ATO binds to Hsp60, leading to abolishment of Hsp60 refolding capability. Significantly, the binding of ATO to Hsp60 disrupts the formation of Hsp60-p53 and Hsp60-survivin complexes, resulting in degradation of p53 and survivin. This study provides significant insights into the mechanism of action of ATO at a systemic perspective, and serves as guidance for the rational design of metal-based anticancer drugs.