A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

Sung Kyun Ko; Jiyeon Kim; Deuk Chae Na; Sookil Park; Seong Hyun Park; Ji Young Hyun; Kyung Hwa Baek; Nam Doo Kim; Nak Kyoon Kim; Young Nyun Park; Kiwon Song; Injae Shin

doi:10.1016/j.chembiol.2015.02.004

A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

Sung Kyun Ko, Jiyeon Kim, Deuk Chae Na, Sookil Park, Seong Hyun Park, Ji Young Hyun, Kyung Hwa Baek, Nam Doo Kim, Nak Kyoon Kim, Young Nyun Park, Kiwon Song, Injae Shin

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

Abstract

Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.

Original language	English
Article number	3008
Pages (from-to)	391-403
Number of pages	13
Journal	Chemistry and Biology
Volume	22
Issue number	3
DOIs	https://doi.org/10.1016/j.chembiol.2015.02.004
Publication status	Published - 2015 Mar 19

Bibliographical note

Funding Information:
This work was supported by grants from the National Creative Research Initiative (grant no. 2010-0018272 to I.S.) program and the National R&D program for Cancer Control (grant no. NCCR-0920300). A part of this work was carried out with support from the Korea government (MSIP) (grant no. NRF-2013R1A2A2A05005990 to Y.N.P.).

Publisher Copyright:
© 2015 Elsevier Ltd All rights reserved.

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2015.02.004

Cite this

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title = "A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities",

abstract = "Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.",

author = "Ko, {Sung Kyun} and Jiyeon Kim and Na, {Deuk Chae} and Sookil Park and Park, {Seong Hyun} and Hyun, {Ji Young} and Baek, {Kyung Hwa} and Kim, {Nam Doo} and Kim, {Nak Kyoon} and Park, {Young Nyun} and Kiwon Song and Injae Shin",

note = "Funding Information: This work was supported by grants from the National Creative Research Initiative (grant no. 2010-0018272 to I.S.) program and the National R&D program for Cancer Control (grant no. NCCR-0920300). A part of this work was carried out with support from the Korea government (MSIP) (grant no. NRF-2013R1A2A2A05005990 to Y.N.P.). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd All rights reserved.",

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doi = "10.1016/j.chembiol.2015.02.004",

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AU - Hyun, Ji Young

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AU - Kim, Nak Kyoon

AU - Park, Young Nyun

AU - Song, Kiwon

AU - Shin, Injae

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Y1 - 2015/3/19

N2 - Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.

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A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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