Heat shock protein 90 inhibitors augment endogenous wild-type p53 expression but down-regulate the adenovirally-induced expression by inhibiting a proteasome activity
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Kuan Chai1,2, Xuerao Ning1,2, Thảo Thi Thanh Nguyễn1,3, Boya Zhong1,3, Takao Morinaga1, Zhihan Li1,3, Masato Shingyoji4, Yuji Tada5, Koichiro Tatsumi5, Hideaki Shimada6, Kenzo Hiroshima7, Naoto Yamaguchi2 and Masatoshi Tagawa1,3
1Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chuo-ku, Chiba 260-8717, Japan
2Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan
3Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan
4Division of Respirology, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
5Department of Respirology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan
6Department of Surgery, School of Medicine, Toho University, Tokyo 143-8540, Japan
7Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo 276-8524, Japan
Masatoshi Tagawa, email: [email protected]
Keywords: adenovirus; p53; HSP90 inhibitor; proteasome
Received: November 07, 2017 Accepted: May 01, 2018 Published: May 25, 2018
Heat shock protein 90 (HSP90) inhibitors suppressed MDM4 functions which mediated p53 ubiquitination, and blocked a chaperon function which influenced expression of the client proteins. We examined cytotoxic effects of the inhibitors, 17-allylamino-17-demetheoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG), on mesothelioma and investigated combinatory effects of the inhibitors and adenoviruses expressing the wild-type p53 gene (Ad-p53). A majority of mesothelioma lacks p14 and p16 expression, which leads to defective p53 pathway despite bearing the wild-type p53 genotype. The HSP90 inhibitors up-regulated endogenous wild-type p53 expression and induced cell death. Furthermore, the inhibitors increased the endogenous p53 levels that were induced by cisplatin. Nevertheless, the HSP90 inhibitors suppressed Ad-p53-induced exogenous p53 expression primarily at a posttranscriptional level and inhibited the Ad-p53-mediated cell death. HSP90 inhibitors suppressed ubiquitination processes which were involved in p53 degradation, but a proteasome inhibitor, MG-132, prevented the HSP90 inhibitors-induced p53 down-regulation. In contrast, an inhibitor for HSP70 with a chaperon function, pifithrin-μ, did not produce the p53 down-regulation. The HSP90 inhibitors did not suppress expression of Ad receptor molecules but rather increased expression of green fluorescence protein transduced by the same Ad vector. These data collectively indicated that an HSP90 inhibitor possessed a divalent action on p53 expression, as an activator for endogenous wild-type p53 through inhibited ubiquitination and a negative regulator of exogenously over-expressed p53 through the proteasome pathway.
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