BAP1 status determines the sensitivity of malignant mesothelioma cells to gemcitabine treatment

Guazzelli, A, Meysami, P, Bakker, E, Demonacos, C, Giordano, A, Krstic- Demonacos, M ORCID: https://orcid.org/0000-0002-3914-4488 and Mutti, L 2019, 'BAP1 status determines the sensitivity of malignant mesothelioma cells to gemcitabine treatment' , International Journal of Molecular Sciences, 20 (2) , p. 429.

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Abstract

Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA associated protein 1 gene BAP1 in the development of MMe. In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed. The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine. Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine. Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells. Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells. Effects on the population of cells in late apoptosis, which can mark necrosis and necroptosis, could not be seen in the mutant cells, highlighting the possibility that BAP1 plays a role in several types of cell death. Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions. After BAP1 silencing, a significant decrease in DNA damage in the form of double-strand breaks was observed compared to cells transfected with scrambled siRNA. Taken together, the results presented in this manuscript shed light on the role of BAP1 in the response of MMe cells to gemcitabine treatment and in particular in the control of the DNA damage response, therefore providing a potential route for more efficient MMe therapy.

Item Type: Article
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: International Journal of Molecular Sciences
Publisher: MDPI
ISSN: 1422-0067
Related URLs:
Funders: Gruppo Italiano Mesotelioma (GIMe)
Depositing User: M Krstic- Demonacos
Date Deposited: 28 Jan 2019 15:36
Last Modified: 06 Feb 2020 10:46
URI: http://usir.salford.ac.uk/id/eprint/49904

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