May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
The Hsp90 Inhibitors, 17-aag and 17-dmag Target Wild-Type B-raf Signaling for the Proliferation of Human Uveal Melanoma Cells
Author Affiliations & Notes
  • N. Babchia
    UMR S 872, Centre de recherche des cordeliers, Université Pierre et Marie Curie-Paris6, Paris, France
  • A. Calipel
    UMR S 872, Centre de recherche des cordeliers, Université Pierre et Marie Curie-Paris6, Paris, France
    Service Universitaire d'Ophtalmologie, Caen, France
  • F. Mouriaux
    Service Universitaire d'Ophtalmologie, Caen, France
  • A. M. Faussat
    UMR S 872, Centre de recherche des cordeliers, Université Pierre et Marie Curie-Paris6, Paris, France
  • F. Mascarelli
    UMR S 872, Centre de recherche des cordeliers, Université Pierre et Marie Curie-Paris6, Paris, France
  • Footnotes
    Commercial Relationships  N. Babchia, None; A. Calipel, None; F. Mouriaux, None; A.M. Faussat, None; F. Mascarelli, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1311. doi:https://doi.org/
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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)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : These data suggest that HSP90 is a potential target for therapeutic strategies against uveal melanoma.

Keywords: melanoma • signal transduction 
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