Chua Vivian, Han Anna, Bechtel Nelisa, Purwin Timothy J, Hunter Emily, Liao Connie, Harbour J William, Aplin Andrew E
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
Pigment Cell Melanoma Res. 2022 Jan;35(1):78-87. doi: 10.1111/pcmr.13007. Epub 2021 Aug 12.
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.
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基因的失活突变导致BRCA1相关蛋白1（BAP1）缺失与UM进展相关。因此，由BAP1功能障碍引起的分子改变可能是转移性UM的新型治疗靶点。在这里，我们发现与BAP1未改变（或野生型[WT]）的UM肿瘤相比，BAP1改变（或突变）的UM肿瘤中AMP依赖激酶（AMPK）的磷酸化水平升高。作为AMPK途径激活的指标，AMPK下游效应物乙酰辅酶A羧化酶（ACC）的磷酸化水平也升高。在BAP1缺失的UM细胞系中重新表达BAP1可降低磷酸化AMPK（pAMPK）和磷酸化ACC（pACC）水平。在BAP1突变的UM细胞中，AMPK磷酸化由钙/钙调蛋白依赖性蛋白激酶激酶2（CaMKK2）以及可能由肝脏激酶B1（LKB1）介导。敲低AMPKα1/2可降低BAP1突变的UM细胞的活力，表明AMPK在BAP1突变的UM中具有生存功能。我们的数据表明，AMPK途径是介导BAP1突变的UM生存的重要机制。靶向AMPK途径可能是转移性UM的一种新型治疗策略。
