Overcoming HSP27-mediated resistance by altered dimerization of HSP27 using small molecules
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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
Yun-Sil Lee, email: firstname.lastname@example.org
Younghwa Na, email: email@example.com
Keywords: HSP27 inhibition, altered dimerization, overcoming resistance, combination therapy
Received: January 04, 2016 Accepted: July 06, 2016 Published: July 16, 2016
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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