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. 2022 Jan;35(1):78-87.
doi: 10.1111/pcmr.13007. Epub 2021 Aug 12.

The AMP-dependent kinase pathway is upregulated in BAP1 mutant uveal melanoma

Vivian Chua  1 , Anna Han  1 , Nelisa Bechtel  1 , Timothy J Purwin  1 , Emily Hunter  1 , Connie Liao  1 , J William Harbour  2 , Andrew E Aplin  1   3
Affiliations

The AMP-dependent kinase pathway is upregulated in BAP1 mutant uveal melanoma

Vivian Chua et al. Pigment Cell Melanoma Res. 2022 Jan.

Abstract

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.

Keywords: AMPK; BAP1; stress; uveal melanoma.

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References

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