Abstract
AIMS, MATERIALS & METHODS: As heat-shock proteins are associated with tumor proliferation, differentiation, invasion and metastasis, we investigated whether targeting Hsp90 with the geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) can inhibit the viability of hepatocellular carcinoma cell lines with various levels of metastatic potential. In addition, we investigated whether the use of Hsp27-siRNA can decrease resistance to 17AAG.
Results:
Although 17AAG upregulated the expression of heat-shock proteins, it did not affect the expression of Hsp90 client proteins in normal hepatocytes. Hsp90 inhibition by 17AAG degraded its client proteins in both low- and high-metastatic potential cell lines. siRNA inhibited Hsp27 expression in cell lines and improved the sensitivity of 17AAG.
Conclusion:
17AAG inhibited the viability of hepatocellular carcinoma cells by degrading Hsp90 client proteins. The sensitivity of cells to 17AAG is associated with the level of Hsp27 expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Benzoquinones / pharmacology*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Cell Survival / drug effects
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Drug Resistance, Neoplasm
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Gene Expression
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Gene Knockdown Techniques
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HSP27 Heat-Shock Proteins / genetics
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HSP27 Heat-Shock Proteins / metabolism*
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HSP70 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / metabolism
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Heat-Shock Proteins
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Hep G2 Cells
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Humans
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Inhibitory Concentration 50
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Lactams, Macrocyclic / pharmacology*
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Molecular Chaperones
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
Substances
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Antineoplastic Agents
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Benzoquinones
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HSP27 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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HSPB1 protein, human
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Heat-Shock Proteins
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Lactams, Macrocyclic
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Molecular Chaperones
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RNA, Small Interfering
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tanespimycin
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3