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Int J Mol Sci. 2019 Jan 19;20(2). pii: E429. doi: 10.3390/ijms20020429.

BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment.

Author information

1
School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK. a.guazzelli@edu.salford.ac.uk.
2
School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK. p.meysami@salford.ac.uk.
3
School of Medicine, University of Central Lancashire, Preston PR1 2HE, UK. ebakker@uclan.ac.uk.
4
Faculty of Biology, Medicine and Health, School of Health Sciences, University of Manchester, Manchester M13 9PL, UK. constantinos.demonacos@manchester.ac.uk.
5
Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy. antonio.giordano@unisi.it.
6
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA. antonio.giordano@unisi.it.
7
School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK. m.krstic-demonacos@salford.ac.uk.
8
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA. chairman@gime.it.

Abstract

Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA1 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 scramble 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.

KEYWORDS:

BAP1; DNA damage; apoptosis; cell cycle; chemoresistance; gemcitabine; malignant mesothelioma

PMID:
30669483
PMCID:
PMC6359027
DOI:
10.3390/ijms20020429
[Indexed for MEDLINE]
Free PMC Article

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