17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels.
Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes growth factor receptors and signaling molecules. Disruption of this action inhibits the MAPK and phosphatidylinositol-3 kinase cascades and can induce cancer cell death. The goal of this study was to determine whether thyroid cancer cells are sensitive to the cytotoxic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor in clinical trials, and to determine predictors of this response. Papillary (NPA), follicular (WRO), and anaplastic (ARO) thyroid cancers were incubated with 17-AAG in vitro. Surprisingly, the ARO cells were most sensitive to the cytotoxic effects of this agent. Conversely, all cell lines displayed similar responses to specific blockers of phosphatidylinositol-3 kinase and MAPK kinase (LY294002 and U0126, respectively). Western blot demonstrated that the NPA cells that were most resistant to 17AAG-induced cytotoxicity had the lowest levels of Hsp90 and were the only cells with persistent levels of Akt protein. Interestingly, even the WRO and ARO cell lines that were sensitive to 17-AAG-induced cell death did not undergo apoptosis. These data suggest that sensitivity of thyroid cancer cells to 17-AAG-induced cytotoxicity relates to Hsp90 levels rather than histological subtype and that thyroid cancer cells have a reduced apoptotic response to 17-AAG.
Braga-Basaria
Milena
M
Section of Endocrinology, Washington Hospital Center/MedStar Research Institute, Washington, DC 20010, USA.
Hardy
Elena
E
Gottfried
Robert
R
Burman
Kenneth D
KD
Saji
Motoyasu
M
Ringel
Matthew D
MD
D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011518:Proto-Oncogene Proteins; D017828:Rifabutin; C112765:tanespimycin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt