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Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine

Johnson, Charlotte, Hunt, David K., Wiltshire, Marie, Herbert, Terry P., Sampson, Julian Roy, Errington, Rachel J., Davies, David Mark and Tee, Andrew 2014. Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine. Molecular Oncology 9 (3) , pp. 675-688. 10.1016/j.molonc.2014.11.005

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Abstract

Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug‐induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper‐active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper‐active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper‐active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1‐driven tumours.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: Available online 22 November 2014 This journal has an embargo period of 12 months PDF uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/1574-7891/ (accessed 1.4.16)
Publisher: Elsevier
ISSN: 1574-7891
Date of First Compliant Deposit: 31 March 2016
Date of Acceptance: 18 November 2014
Last Modified: 27 Jun 2019 11:15
URI: http://orca.cf.ac.uk/id/eprint/88485

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