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N. Babchia, A. Calipel, F. Mouriaux, A. M. Faussat, F. Mascarelli; The Hsp90 Inhibitors, 17-aag and 17-dmag Target Wild-Type B-raf Signaling for the Proliferation of Human Uveal Melanoma Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1311. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The HSP90 inhibitor, 17-AAG, has been shown promising results in antitumor activity through the degradation of the activated V600E mutant of B-Raf (V600EB-Raf) in cutaneous melanoma cell lines. In contrast 17-AAG has different effects on the wild-type form of B-Raf (WTB-Raf), depending on the activation levels of WTB-Raf in these cells. Uveal melanoma cells express WTB-Raf and rarely V600EB-Raf. This study was conducted to investigate the effects of HSP90 inhibition on uveal melanoma cell lines.
Human uveal melanoma cell lines were treated with the HSP90 inhibitors, 17-AAG and 17-DMAG. Cell proliferation was assessed by MTT-staining, and apoptosis was quantified by flow cytometry. Analysis of the expression of HSP90 and activation of the MEK/ERK downstream signaling of B-Raf was performed by western blot. The effects of the downregulation of the co-chaperone of HSP90, cdc37, on cell proliferation and activation of MEK/ERK was investigated by si RNA strategy.
Inhibition of HSP90 downregulated B-Raf, decreased cell proliferation and reduced activation of MEK/ERK in uveal melanoma cell lines expressing WTB-Raf. HSP90 inhibition also reduced the expression of Akt, but inhibition of Akt had no effect on cell proliferation, ruling out a role of Akt in the 17-AAG-induced inhibition of cell proliferation. Downregulation of cdc37 did not affect the MEK/ERK signalling and cell proliferation, demonstrating that the co-chaperone was not required for HSP90-controlled stability of B-Raf. C-Kit was also downregulated following HSP90 inhibition. The combination of 17-DMAG with imatinib mesylate, the inhibitor of c-kit, had synergistic inhibitory effects on cell proliferation in WTB-Raf uveal melanoma cell lines.
These data suggest that HSP90 is a potential target for therapeutic strategies against uveal melanoma.
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