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

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.

• Authors: Jee Hye Kim, Ye Jin Jung, Byeol Choi, Na Lim Lee, Hae Jun Lee, Soo Yeon Kwak, Youngjoo Kwon, Younghwa Na, Yun-Sil Lee
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 33 Pg. 53178-53190 (Aug 16 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27449291 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzoquinones
• HSP27 Heat-Shock Proteins
• Lactams, Macrocyclic
• Small Molecule Libraries
• Xanthones
• tanespimycin

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzoquinones (administration & dosage)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics, radiation effects)
• Chemoradiotherapy
• HSP27 Heat-Shock Proteins (antagonists & inhibitors, chemistry, genetics)
• Humans
• Kaplan-Meier Estimate
• Lactams, Macrocyclic (administration & dosage)
• Lung Neoplasms (metabolism, pathology, therapy)
• Mice, Inbred BALB C
• Mice, Nude
• Protein Multimerization (drug effects)
• RNA Interference
• Small Molecule Libraries (chemistry, pharmacology)
• Xanthones (administration & dosage, chemistry, pharmacology)
• Xenograft Model Antitumor Assays