Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells - Université Côte d'Azur Access content directly
Journal Articles Cell Death Discovery Year : 2020

Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells

Abstract

To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.
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Dates and versions

hal-02954739 , version 1 (01-10-2020)

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Lara Bellini, Thomas Strub, Nadia Habel, Charlotte Pandiani, Sandrine Marchetti, et al.. Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells. Cell Death Discovery, 2020, 6, pp.22. ⟨10.1038/s41420-020-0259-2⟩. ⟨hal-02954739⟩
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