Oncotarget

Research Papers:

Overcoming HSP27-mediated resistance by altered dimerization of HSP27 using small molecules

Jee Hye Kim, Ye Jin Jung, Byeol Choi, Na Lim Lee, Hae Jun Lee, Soo Yeon Kwak, Youngjoo Kwon, Younghwa Na and Yun-Sil Lee _

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Oncotarget. 2016; 7:53178-53190. https://doi.org/10.18632/oncotarget.10629

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Abstract

Jee Hye Kim1,*, Ye Jin Jung1,*, Byeol Choi1, Na Lim Lee1, Hae Jun Lee2, Soo Yeon Kwak3, Youngjoo Kwon1, Younghwa Na3, Yun-Sil Lee1

1Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-720, Korea

2Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Korea

3College of Pharmacy, CHA University, Pocheon, 487-010, Korea

*These authors contributed equally to this work

Correspondence to:

Yun-Sil Lee, email: yslee0425@ewha.ac.kr

Younghwa Na, email: yna7315@cha.ac.kr

Keywords: HSP27 inhibition, altered dimerization, overcoming resistance, combination therapy

Received: January 04, 2016     Accepted: July 06, 2016     Published: July 16, 2016

ABSTRACT

Heat shock protein 27 (HSP27, HSPB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. The biochemical properties of HSP27 rely on a structural oligomeric and dynamic organization that is important for its chaperone activity. Down-regulation by small interfering RNA or inhibition with a dominant-negative mutant efficiently counteracts the anti-apoptotic and protective properties of HSP27. However, unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, we found that a small molecule, zerumbone (ZER), induced altered dimerization of HSP27 by cross linking the cysteine residues required to build a large oligomer, led to sensitization in combination with radiation. In this study, we identified another small molecule, a xanthone compound, more capable of altering dimeric HSP27 than ZER and yielding sensitization in human lung cancer cells when combined with HSP90 inhibitors or standard anticancer modalities such as irradiation and cytotoxic anticancer drugs. Therefore, altered dimerization of HSP27 represents a good strategy for anticancer therapy in HSP27-overexpressing cancer cells.


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