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; Mutti, L

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.

Citation

Guazzelli, A., Meysami, P., Bakker, E., Demonacos, C., Giordano, A., Krstic- Demonacos, M., & Mutti, L. (2019). BAP1 status determines the sensitivity of malignant mesothelioma cells to gemcitabine treatment. International Journal of Molecular Sciences, 20(2), 429. https://doi.org/10.3390/ijms20020429

• Journal Article Type: Article
• Acceptance Date: Jan 12, 2019
• Online Publication Date: Jan 19, 2019
• Publication Date: Jan 19, 2019
• Deposit Date: Jan 28, 2019
• Publicly Available Date: Jan 28, 2019
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Publisher: MDPI
• Volume: 20
• Issue: 2
• Pages: 429
• DOI: https://doi.org/10.3390/ijms20020429
• Publisher URL: https://doi.org/10.3390/ijms20020429
• Related Public URLs: https://www.mdpi.com/journal/ijms
• Additional Information: Projects : BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment