X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition

被引:48
作者
Cesa, Laura C. [1 ]
Shao, Hao [5 ]
Srinivasan, Sharan R. [1 ]
Tse, Eric [3 ,4 ]
Jain, Chetali [2 ]
Zuiderweg, Erik R. P. [3 ]
Southworth, Daniel R. [1 ,3 ,4 ]
Mapp, Anna K. [1 ,2 ,4 ]
Gestwicki, Jason E. [5 ]
机构
[1] Univ Michigan, Program Chem Biol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA
[5] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA
基金
美国国家卫生研究院;
关键词
MOLECULAR CHAPERONES; ONCOGENE ADDICTION; SUBSTRATE-BINDING; CO-CHAPERONES; HSP90; CANCER; REVEALS; DEGRADATION; DNAK; COMPLEX;
D O I
10.1074/jbc.RA117.000634
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Heat shock protein 70 (Hsp70) and Hsp90 are molecular chaperones that play essential roles in tumor growth by stabilizing pro-survival client proteins. However, although the development of Hsp90 inhibitors has benefited from the identification of clients, such as Raf-1 proto-oncogene, Ser/Thr kinase (RAF1), that are particularly dependent on this chaperone, no equivalent clients for Hsp70 have been reported. Using chemical probes and MDA-MB-231 breast cancer cells, we found here that the inhibitors of apoptosis proteins, including c-IAP1 and X-linked inhibitor of apoptosis protein (XIAP), are obligate Hsp70 clients that are rapidly (within similar to 3-12 h) lost after inhibition of Hsp70 but not of Hsp90. Mutagenesis and pulldown experiments revealed multiple Hsp70-binding sites on XIAP, suggesting that it is a direct, physical Hsp70 client. Interestingly, this interaction was unusually tight (similar to 260 nM) for an Hsp70-client interaction and involved non-canonical regions of the chaperone. Finally, we also found that Hsp70 inhibitor treatments caused loss of c-IAP1 and XIAP in multiple cancer cell lines and in tumor xenografts, but not in healthy cells. These results are expected to significantly accelerate Hsp70 drug discovery by providing XIAP as a pharmacodynamic biomarker. More broadly, our findings further suggest that Hsp70 and Hsp90 have partially non-overlapping sets of obligate protein clients in cancer cells.
引用
收藏
页码:2370 / 2380
页数:11
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