Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT.
The molecular chaperone complex Hsp90-p23 interacts with the rate-limiting catalytic subunit of telomerase, hTERT. Although their interactions are required for proper folding of nascent hTERT as well as the assembly of active telomerase, the precise role of the chaperone proteins in regulation of nuclear localization of hTERT remains unclear. Here we demonstrate that curcumin inhibits telomerase activity in a time- and dose-dependent manner by decreasing the level of hTERT expression. Following curcumin treatment, we observed a clear accumulation of hTERT in the cytoplasmic compartment of the cell. The curcumin-induced cytoplasmic retention of hTERT could be due to failure of nuclear import, and the resulting cytoplasmic hTERT protein was rapidly ubiquitinated and degraded by the proteasome. We also report that curcumin treatment results in a substantial decrease in association of p23 and hTERT but does not affect the Hsp90 binding to hTERT. In contrast, the treatment of the Hsp90 inhibitor geldanamycin promotes dissociation of both Hsp90 and p23 proteins from hTERT. Taken together, these results demonstrate that the interaction of the Hsp90-p23 complex with hTERT is critical for regulation of the nuclear localization of telomerase, and that down-regulation of hTERT by curcumin involves dissociating the binding of hTERT with p23. Thus, inhibition of nuclear translocation of hTERT by curcumin may provide new perspectives for regulation of telomerase activity during tumorigenic progression.
Lee
Ji Hoon
JH
Departments of Biology and Biomedical Sciences, Yonsei University, Seoul, Republic of Korea.
Chung
In Kwon
IK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D003474:Curcumin / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019746:Intramolecular Oxidoreductases / Q000187:drug effects* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D021381:Protein Transport / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D019098:Telomerase; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D003474:Curcumin