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D. Faingold, D. A. Abourbih, E. Antecka, B. F. Fernandes, Z. M. S. Correa, M. N. Burnier, Jr.; Immune Expression and Inhibition of Hsp90 in Metastatic Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):77. doi: https://doi.org/.
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Heat shock protein 90 (Hsp90) is a chaperone for many key regulators involved in signal transduction and cell cycle control during malignant transformation. Previous data showed that expression of Hsp90 in uveal melanoma (UM) correlated with largest tumor dimension and inhibition of Hsp90 had an effect on cell motility and invasive potential. We further examined the expression of Hsp90 in metastatic UM and determined the effect of Hsp90 inhibitor, 17-AAG, on the proliferation of metastatic cells.
The expression of Hsp90, was studied in one metastatic derived uveal melanoma cell line, OMM-1.5, by Western blot analysis and immunofluorescence. In addition, 5 human UM metastatic specimens and 14 metastatic specimens from an animal model of UM were also immunostained. Sulforhodamine-B based proliferation assay was used to compare OMM-1.5 cell growth with a range of concentrations of 17-AAG from 100µM to 0.001µM. Expression of Met and IGF1R was determined by Western blot analysis in primary uveal melanoma cell lines 92.1, OCM-1, MKT-BR and SP6.5 treated with 10µM of 17-AAG for 24h, 48h and 72h.
Hsp90 was expressed in OMM-1.5 cells, in 4 of the 5 (80%) metastatic lesions from patients and in 10 of the 14 (71%) metastatic sections from the animal model. A statistically significant reduction in proliferation rate of the cells from the OMM-1.5 cell line was observed with concentrations of 100 µM to 1 µM of 17-AAG (p<0.05). Drug exposure was associated with decreased levels of Met and IGF1R in primary uveal melanoma cell lines after 24 h.
To the best of our knowledge, this is the first report demonstrating that Hsp90 is expressed in metastatic UM. Moreover, inhibition of Hsp90 downregulates the proliferation of metastatic UM cells. We also showed that 17-AAG downregulated Met and IGF1R receptor tyrosine kinases, which are implicated in the metastatic process. These data suggest that Hsp90 inhibitors can be used as therapeutic agents that target cellular processes involved in invasion and metastasis of UM.
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