Oncotarget

Research Papers:

The anti-apoptotic BAG3 protein is involved in BRAF inhibitor resistance in melanoma cells

Luana Guerriero, Giuseppe Palmieri, Margot De Marco, Antonio Cossu, Paolo Remondelli, Mario Capunzo, Maria Caterina Turco and Alessandra Rosati _

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Oncotarget. 2017; 8:80393-80404. https://doi.org/10.18632/oncotarget.18902

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Abstract

Luana Guerriero1, Giuseppe Palmieri2, Margot De Marco1, Antonio Cossu3, Paolo Remondelli4, Mario Capunzo4, Maria Caterina Turco1,4 and Alessandra Rosati1,4

1BIOUNIVERSA s.r.l., 84084 Baronissi, Italy

2Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 07100 Sassari, Italy

3Unit of Pathology, Azienda Ospedaliero Universitaria (AOU), University di Sassari, 07100 Sassari, Italy

4Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana” University of Salerno, 84084 Baronissi, Italy

Correspondence to:

Alessandra Rosati, email: arosati@unisa.it

Keywords: BAG3, melanoma, BRAF, vemurafenib, resistance

Received: January 20, 2017     Accepted: June 13, 2017     Published: June 30, 2017

ABSTRACT

BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-γ levels, allowing a sustained activation of NF-κB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas. BRAFV600E is the most frequent mutation detected in malignant melanomas and is targeted by Vemurafenib, a specific inhibitor found to be effective in the treatment of advanced melanoma. However, patients with BRAF-mutated melanoma may result insensitive ab initio or, mostly, develop acquired resistance to the treatment with this molecule.

Here we show that BAG3 down-modulation interferes with BRAF levels in melanoma cells and sensitizes them to Vemurafenib treatment. Furthermore, the down-modulation of BAG3 protein in an in vitro model of acquired resistance to Vemurafenib can induce sensitization to the BRAFV600E specific inhibition by interfering with BRAF pathway through reduction of ERK phosphorylation, but also on parallel survival pathways.

Future studies on BAG3 molecular interactions with key proteins responsible of acquired BRAF inhibitor resistance may represent a promising field for novel multi-drugs treatment design.


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