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 | |
| Publication status | Published - 2015 Mar 19 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Clinical Biochemistry
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A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities. / Ko, Sung Kyun; Kim, Jiyeon; Na, Deuk Chae; Park, Sookil; Park, Seong Hyun; Hyun, Ji Young; Baek, Kyung Hwa; Kim, Nam Doo; Kim, Nak Kyoon; Park, Young Nyun; Song, Kiwon; Shin, Injae.
In: Chemistry and Biology, Vol. 22, No. 3, 3008, 19.03.2015, p. 391-403.Research output: Contribution to journal › Article
TY - JOUR
T1 - A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities
AU - Ko, Sung Kyun
AU - Kim, Jiyeon
AU - Na, Deuk Chae
AU - Park, Sookil
AU - Park, Seong Hyun
AU - Hyun, Ji Young
AU - Baek, Kyung Hwa
AU - Kim, Nam Doo
AU - Kim, Nak Kyoon
AU - Park, Young Nyun
AU - Song, Kiwon
AU - Shin, Injae
PY - 2015/3/19
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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84925463299&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2015.02.004
DO - 10.1016/j.chembiol.2015.02.004
M3 - Article
C2 - 25772468
AN - SCOPUS:84925463299
VL - 22
SP - 391
EP - 403
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 3
M1 - 3008
ER -