Abstract
The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compounds, we have discovered that small-cell lung carcinoma is a distinctive cellular system in which apoptosis is mainly regulated by Hsp90. Unlike the well-characterized antiapoptotic chaperone Hsp70, Hsp90 is not a general inhibitor of apoptosis, but it assumes this role in systems such as small-cell lung carcinoma, in which apoptosis is uniquely dependent on and effected through the intrinsic pathway, without involvement of caspase elements upstream of mitochondria or alternate pathways that are not apoptosome-channeled. These results provide important evidence for a transformation-specific interplay between chaperones in regulating apoptosis in malignant cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis*
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Carcinoma, Small Cell / drug therapy*
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Carcinoma, Small Cell / metabolism*
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Carcinoma, Small Cell / pathology
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Cell Line, Tumor
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Cell Transformation, Neoplastic
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic
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HSP90 Heat-Shock Proteins / metabolism*
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Models, Chemical
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Phosphatidylinositol 3-Kinases / metabolism
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Time Factors
Substances
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Antineoplastic Agents
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HSP90 Heat-Shock Proteins
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Phosphatidylinositol 3-Kinases
Associated data
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PubChem-Substance/24769879
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PubChem-Substance/24769880
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PubChem-Substance/24769881
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PubChem-Substance/24769882
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PubChem-Substance/24769883
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PubChem-Substance/24769884
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PubChem-Substance/24769885
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PubChem-Substance/24769886
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PubChem-Substance/24769887
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PubChem-Substance/24769888
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PubChem-Substance/24769889
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PubChem-Substance/24769890
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PubChem-Substance/24769891
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PubChem-Substance/24769892
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PubChem-Substance/24769893
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PubChem-Substance/24769894
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PubChem-Substance/24769895
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PubChem-Substance/24769896
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PubChem-Substance/24769897
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PubChem-Substance/24769898
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PubChem-Substance/24769899
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PubChem-Substance/24769900
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PubChem-Substance/24769901
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PubChem-Substance/24769902
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PubChem-Substance/24769903
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PubChem-Substance/24769904
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PubChem-Substance/24769905
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PubChem-Substance/24769906
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PubChem-Substance/24769907
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PubChem-Substance/24769908
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PubChem-Substance/24769909
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PubChem-Substance/24769910
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PubChem-Substance/24769911
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PubChem-Substance/24769912