Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer

Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment...

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Main Authors:	MA, LIANG, SATO, FUMINORI, SATO, RYUTA, MATSUBARA, TAKANORI, HIRAI, KENICHI, YAMASAKI, MUTSUSHI, SHIN, TOSHITAKA, SHIMADA, TATSUO, NOMURA, TAKEO, MORI, KENICHI, SUMINO, YASUHIRO, MIMATA, HIROMITSU
Format:	Online
Language:	English
Published:	D.A. Spandidos 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055347/

id	pubmed-4055347
recordtype	oai_dc
spelling	pubmed-40553472014-06-13 Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer MA, LIANG SATO, FUMINORI SATO, RYUTA MATSUBARA, TAKANORI HIRAI, KENICHI YAMASAKI, MUTSUSHI SHIN, TOSHITAKA SHIMADA, TATSUO NOMURA, TAKEO MORI, KENICHI SUMINO, YASUHIRO MIMATA, HIROMITSU Articles Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer. D.A. Spandidos 2014-06 2014-04-09 /pmc/articles/PMC4055347/ /pubmed/24718854 http://dx.doi.org/10.3892/or.2014.3132 Text en Copyright © 2014, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	MA, LIANG SATO, FUMINORI SATO, RYUTA MATSUBARA, TAKANORI HIRAI, KENICHI YAMASAKI, MUTSUSHI SHIN, TOSHITAKA SHIMADA, TATSUO NOMURA, TAKEO MORI, KENICHI SUMINO, YASUHIRO MIMATA, HIROMITSU
spellingShingle	MA, LIANG SATO, FUMINORI SATO, RYUTA MATSUBARA, TAKANORI HIRAI, KENICHI YAMASAKI, MUTSUSHI SHIN, TOSHITAKA SHIMADA, TATSUO NOMURA, TAKEO MORI, KENICHI SUMINO, YASUHIRO MIMATA, HIROMITSU Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
author_facet	MA, LIANG SATO, FUMINORI SATO, RYUTA MATSUBARA, TAKANORI HIRAI, KENICHI YAMASAKI, MUTSUSHI SHIN, TOSHITAKA SHIMADA, TATSUO NOMURA, TAKEO MORI, KENICHI SUMINO, YASUHIRO MIMATA, HIROMITSU
author_sort	MA, LIANG
title	Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
title_short	Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
title_full	Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
title_fullStr	Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
title_full_unstemmed	Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
title_sort	dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer
description	Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer.
publisher	D.A. Spandidos
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055347/
_version_	1612100356489084928

Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer

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