title: Heat shock protein 90 inhibitors induce functional inhibition of human natural killer cells in a dose-dependent manner.
abstract: Heat shock protein 90 (Hsp90) is a ubiquitously expressed ATP-dependent molecular chaperone across all species that helps to the correct the folding of many proteins related to important signaling pathways. Tumor cells expressing Hsp90 have more ATP-binding affinity than normal cells. Many correlative inhibitors have been developed to promising anti-tumor strategies and have been evaluated in clinical trials. However, the effect of Hsp90 inhibitors on immunocytes cannot be ignored. Natural killer (NK) cells are key components of the innate immune system that play a pivotal role in tumor surveillance. The present study has investigated the potential effect of four Hsp90 inhibitors (NVP-AUY922, BIIB021, 17-DMAG, and SNX-2112) on human primary NK cells. The viability, cytotoxicity, apoptosis, phenotype, and cytokine secretion of NK cells after inhibitor treatment were assessed. The results of this study demonstrated that the inhibitors had negative effects on NK cell activity in a dose-dependent manner. The four inhibitors significantly reduced the cytotoxicity of the NK cells by decreasing viability, inducing apoptosis and down-regulating the expression of cytokines and functional receptors. These findings suggest that more attention should be given to the effect of Hsp90 inhibitors on NK cell function during clinical trials and also represent a potential immunosuppressant strategy.
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Huyan
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Dong
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Huang
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Da-Chuan
authors.initials: DC
authors.lastname: Yin
authors.affiliation: a Key Laboratory for Space Bioscience and Space Biotechnology, School of Life Sciences, Northwestern Polytechnical University , Xi'an, Shaanxi , People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Shang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; D016227:Benzoquinones; D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D011725:Pyridines; D012118:Resorcinols; C534922:SNX 2112; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000225:Adenine
keywords: Apoptosis; Hsp90 inhibitors; cytotoxicity; human natural killer cells; immunotherapy