title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: McCloy
authors.forename: E J
authors.initials: EJ
authors.lastname: Shelley
authors.forename: C G
authors.initials: CG
authors.lastname: Roberts
authors.forename: E
authors.initials: E
authors.lastname: Boslem
authors.forename: T J
authors.initials: TJ
authors.lastname: Biden
authors.forename: R I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: J M
authors.initials: JM
authors.lastname: Gee
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: E A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: A
authors.initials: A
authors.lastname: Burgess
authors.forename: A J
authors.initials: AJ
authors.lastname: Butt
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005233:Fatty Alcohols / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005233:Fatty Alcohols; D010936:Plant Extracts; D013629:Tamoxifen; C098164:persin