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mTOR modulates resistance to gemcitabine in lung cancer in an MTORC2 dependent mechanism.

Chawsheen, M. A. and Dash, P. R. (2021) mTOR modulates resistance to gemcitabine in lung cancer in an MTORC2 dependent mechanism. Cellular Signalling, 81. 109934. ISSN 0898-6568

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To link to this item DOI: 10.1016/j.cellsig.2021.109934


Lung cancer has a poor prognosis partly due to a lack of response to treatments such as the chemotherapy drug gemcitabine. Combinations of chemotherapy drugs with signal transduction inhibitors may be more effective treatments. In this study we have investigated the impact of targeting the mTOR signalling pathway on the efficacy of gemcitabine in different cancer cell lines. Time-lapse microscopy, immuno-staining, and western blot techniques were used to evaluate the efficacy of applied treatments either in measuring phosphorylation levels of mTOR down-stream targets or in tracking down the fate of targeted cells. Reactive oxygen species and relative levels of protein phosphorylation were also quantified. For comparison between treated groups t-test and analysis of variance test were applied. Our data showed that mTORC1 has no role in sensitising A549 lung cancer cells to gemcitabine. However, targeting mTORC1/2 with the pharmacological inhibitor torin1 or by over-expressing Deptor, the negative regulator of mTOR signalling, sensitised these cells to gemcitabine. Silencing mTORC2, but not mTORC1, induced apoptosis and significantly improved the apoptosis-inducing effects of gemcitabine. Results also suggest that Rictor is required to maintain cell survival through modulating p38α, ERK1/2, RSK1/2/3 and the transcription factor STAT3. Multiple cell line comparisons revealed that PANC-1 pancreatic cancer cells were also sensitive to mTOR inhibition, but MCF7 breast cancer, MCF10A breast epithelial and H727 lung cancer cell lines were more resistant to the treatment. Inhibition of mTORC2 may have benefits in the treatment of gemcitabine resistant cancers, and the genetic background of the cell line may determine its response to mTOR inhibition. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]

Item Type:Article
Divisions:Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:96372
Uncontrolled Keywords:Cell death, Chemotherapy resistance, Gemcitabine, Lung cancer, Reactive oxygen species, Torin1, mTOR, mTORC2

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