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

• Published in: British journal of cancer Vol. 109; no. 12; pp. 3034 - 3041
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.12.2013; Nature Publishing Group
• Subjects: 631/154/349; 631/80/82/23; 692/699/67/1059/2326; 692/699/67/1347; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer Research; Cancer therapies; Cell Line, Tumor; Cytotoxicity; Drug Resistance; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Epidemiology; Fatty Alcohols - administration & dosage; Fatty Alcohols - pharmacology; Female; Gynecology. Andrology. Obstetrics; Humans; Hypoxia; Mammary gland diseases; MCF-7 Cells; Medical research; Medical sciences; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Plant Extracts - pharmacology; Signal Transduction; Tamoxifen - administration & dosage; Tamoxifen - pharmacology; Translational Therapeutics; Tumors; Australia; persin; breast cancer; apoptosis; tamoxifen; endoplasmic reticulum stress; Antineoplastic agent; Breast disease; Antiestrogen; Antihormone; Plant; Selective estrogen receptor modulator; Cancerology; Non steroid compound; Tumor cell; Human; Induction; Breast cancer; Malignant tumor; Stress; Tamoxifene; Resistance; Mammary gland diseases; Toxin; Cell death; Endoplasmic reticulum; Cancer; Apoptosis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.693

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.