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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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https://hal.univ-cotedazur.fr/hal-02954739
Contributor : Bertolotto-Ballotti Bertolotto-Ballotti <>
Submitted on : Thursday, October 1, 2020 - 11:59:59 AM
Last modification on : Monday, October 12, 2020 - 10:28:23 AM
Long-term archiving on: : Monday, January 4, 2021 - 8:42:48 AM

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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, Springer Nature, 2020, 6, pp.22. ⟨10.1038/s41420-020-0259-2⟩. ⟨hal-02954739⟩

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