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CLU blocks HDACI-mediated killing of neuroblastoma. Tumour Biol 2011 Apr;32(2):285-94

Date

11/03/2010

Pubmed ID

21042904

Pubmed Central ID

PMC3041908

DOI

10.1007/s13277-010-0120-y

Scopus ID

2-s2.0-79953772135   2 Citations

Abstract

Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.

Author List

Subramanian C, Jarzembowski JA, Halsey SM, Kuick R, Opipari AW Jr, Castle VP, Kwok RP

Author

Jason A. Jarzembowski MD, PhD Sr Associate Dean, CEO CSG, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylation
Antigens, Nuclear
Apoptosis
Biomarkers, Tumor
Cell Line, Tumor
Cell Survival
Clusterin
DNA-Binding Proteins
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors
Humans
Ku Autoantigen
Neuroblastoma
bcl-2-Associated X Protein