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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


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.

Type Journal
ISBN 1532-1827 (Electronic) 0007-0920 (Linking)
Authors McCloy, R. A. ; Shelley, E. J. ; Roberts, C. G. ; Boslem, E. ; Biden, T. J. ; Nicholson, R. I. ; Gee, J. M. ; Sutherland, R. L. ; Musgrove, E. A. ; Burgess, A. ; Butt, A. J.;
Publisher Name British Journal of Cancer
Published Date 2013-12-01
Published Volume 109
Published Issue 12
Published Pages 3034-41
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version