Metastatic uveal melanoma (UM) responds poorly to targeted therapies and immune checkpoint inhibitors. Loss of BRCA1-associated protein 1 (BAP1) via inactivating mutations in the BAP1 gene is associated with UM progression. Thus, molecular alterations caused by BAP1 dysfunction may be novel therapeutic targets for metastatic UM. Here, we found that phosphorylation of AMP-dependent kinase (AMPK) was elevated in BAP1-altered (or mutant) compared to BAP1-unaltered (or wild-type [WT]) UM tumors. As a readout of AMPK pathway activation, phosphorylation of an AMPK downstream effector, acetyl-CoA-carboxylase (ACC), was also elevated. BAP1 re-expression in BAP1-null UM cell lines decreased phospho-AMPK (pAMPK) and phospho-ACC (pACC) levels. AMPK phosphorylation is mediated by calcium/calmodulin dependent protein kinase kinase 2 (CaMKK2) and potentially liver kinase B1 (LKB1) in BAP1 mutant UM cells. Knockdown of AMPKα1/2 reduced the viability of BAP1 mutant UM cells, indicating a survival function of AMPK in BAP1 mutant UM. Our data suggest that the AMPK pathway is an important mechanism mediating the survival of BAP1 mutant UM. Targeting the AMPK pathway may be a novel therapeutic strategy for metastatic UM.

中文翻译：

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AMP依赖性激酶途径在BAP1突变葡萄膜黑色素瘤中上调

转移性葡萄膜黑色素瘤 (UM) 对靶向治疗和免疫检查点抑制剂反应不佳。通过BAP1基因中的失活突变丢失 BRCA1 相关蛋白 1 (BAP1)与 UM 进展有关。因此，由 BAP1 功能障碍引起的分子改变可能是转移性 UM 的新治疗靶点。在这里，我们发现与BAP1相比，AMP 依赖性激酶 (AMPK) 的磷酸化在BAP1改变（或突变）中升高-未改变（或野生型 [WT]）的 UM 肿瘤。作为 AMPK 通路激活的读数，AMPK 下游效应子乙酰辅酶 A 羧化酶 (ACC) 的磷酸化也升高。BAP1-null UM 细胞系中的 BAP1 重新表达降低了磷酸-AMPK (pAMPK) 和磷酸-ACC (pACC) 水平。AMPK 磷酸化由BAP1突变 UM 细胞中的钙/钙调蛋白依赖性蛋白激酶激酶 2 (CaMKK2) 和潜在的肝激酶 B1 (LKB1) 介导。AMPKα1/2的敲低降低了BAP1突变体 UM 细胞的活力，表明 AMPK 在BAP1突变体 UM 中的存活功能。我们的数据表明AMPK途径是介导BAP1存活的重要机制突变的UM。靶向 AMPK 通路可能是转移性 UM 的一种新的治疗策略。