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Role of endoplasmic reticulum stress induction by the plant toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells

McCloy, R. A., Shelley, E. J., Roberts, C. G., Boslem, E., Biden, T. J., Nicholson, Robert Ian, Gee, Julia Margaret Wendy, Sutherland, R. L., Musgrove, E. A., Burgess, A. and Butt, A. J. 2013. Role of endoplasmic reticulum stress induction by the plant toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells. British Journal of Cancer 109 (12) , pp. 3034-3041. 10.1038/bjc.2013.693

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Abstract

Background: Persin is a plant toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and delineated the intracellular signalling pathways involved. Methods: The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference. Results: Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells. Conclusion: The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: tamoxifen; persin; breast cancer; apoptosis; endoplasmic reticulum stress
Publisher: Nature Publishing Group
ISSN: 0007-0920
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 06:14
URI: http://orca-mwe.cf.ac.uk/id/eprint/57627

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