Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.,Cell Death Discovery

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Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-04-17 , DOI: 10.1038/s41420-020-0259-2
Lara Bellini _{1,

2} , Thomas Strub _{1,

2} , Nadia Habel _{1,

2} , Charlotte Pandiani _{1,

2} , Sandrine Marchetti _{1,

3} , Arnaud Martel _{1,

2,

4} , Stéphanie Baillif _{1,

2,

4} , Béatrice Bailly-Maitre _{1,

5} , Philippe Gual _{1,

5} , Robert Ballotti _{1,

2} , Corine Bertolotto _{1,

2}

Affiliation

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.

中文翻译：

内质网应激介导葡萄膜黑色素瘤细胞对 BCL-2 抑制剂的耐药性。

为了解决葡萄膜黑色素瘤未满足的临床需求，我们评估了 BH3 模拟分子（ABT 家族）的作用，已知该分子在癌细胞中发挥促凋亡活性。我们的结果发现，ABT-263 (Navitoclax) 是一种有效的口服生物可利用的 BCL-2 家族抑制剂，通过将细胞周期阻滞在 G0/G1 期、线粒体膜电位丧失以及随后的转移性人葡萄膜黑色素瘤细胞，诱导抗增殖作用。通过半胱天冬酶激活和聚 ADP 核糖聚合酶裂解监测细胞凋亡。在体内也观察到 ABT-263 介导的肿瘤生长减少。我们在一些细胞中观察到，ABT-263 治疗通过激活 ER 应激信号通路产生促生存反应。阻断 PERK 信号通路可增加 ABT-263 的促凋亡作用。因此，我们发现了葡萄膜黑色素瘤细胞中由内质网应激途径激活介导的抵抗机制。因此，我们的研究确定 ABT-263 是葡萄膜黑色素瘤患者的有效治疗选择。

更新日期：2020-04-24

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