Immune expression and inhibition of heat shock protein 90 in uveal melanoma

Immune expression and inhibition of heat shock protein 90 in uveal melanoma

Author Faingold, Dana Google Scholar
Marshall, Jean-Claude Google Scholar
Antecka, Emilia Google Scholar
Di Cesare, Sebastian Google Scholar
Odashiro, Alexandre N. Google Scholar
Bakalian, Silvin Google Scholar
Fernandes, Bruno F. Google Scholar
Burnier, Miguel N. Autor UNIFESP Google Scholar
Institution McGill Univ
Henry C Witelson Ocular Pathol Lab
Universidade Federal de São Paulo (UNIFESP)
Abstract Purpose: To examine the immunohistochemical profile of heat shock protein 90 (Hsp90) in uveal melanoma and the cytotoxicity of an Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), in uveal melanoma cell lines.Experimental Design: Hsp90 expression was determined by immunohistochemistry in 44 paraffin-embedded sections of primary human uveal melanoma and in five uveal melanoma cell lines (92.1, OCM-1, MKT-BR, SP6.5, and UW-1). Sulforhodamine B-based proliferation assay was used to compare uveal melanoma cell growth with a range of concentrations of 17-AAG. Changes in cell migration, invasion, cell cycle fractions, and apoptotic activity were also evaluated. Expression of intracellular proteins was determined by Western blot analysis after 17-AAG exposure.Results: Immunohistochemical expression of Hsp90 was identified in 68% of the paraffin-embedded sections and significantly associated with largest tumor dimension (P = 0.03). 17-AAG significantly reduced the proliferation rates of uveal melanoma cell lines, with concentrations of 100 to 0.1 mu mol/L. 17-AAG also significantly reduced the migratory and invasive capabilities of uveal melanoma cell lines. Cell cycle analysis showed that 17-AAG induced accumulations of cells in G(1). Caspase-3 protease activity analysis, a marker for apoptosis, showed a significant increase after drug exposure. the cytotoxic effect of 17-AAG was associated with decreased levels of phosphorylated Akt and cyclin-dependent kinase 4.Conclusions: the immunohistochemical expression of Hsp90 in uveal melanoma indicates worse prognosis. To the best of our knowledge, this is the first report showing the inhibitory effect on uveal melanoma cells using 17-AAG to target Hsp90. Therefore, Hsp90 may be used as a potential target for treatment of patients with uveal melanoma.
Language English
Date 2008-02-01
Published in Clinical Cancer Research. Philadelphia: Amer Assoc Cancer Research, v. 14, n. 3, p. 847-855, 2008.
ISSN 1078-0432 (Sherpa/Romeo, impact factor)
Publisher Amer Assoc Cancer Research
Extent 847-855
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000252882400032

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