title: Ophiobolin A, a sesterpenoid fungal phytotoxin, displays different mechanisms of cell death in mammalian cells depending upon the cancer cell origin.
abstract: Herein we have undertaken a systematic analysis of the effects of the fungal derivative ophiobolin A (OphA) on eight cancer cell lines from different tissue types. The LD50 for each cell line was determined and the change in cell size determined. Flow cytometric analysis and western blotting were used to assess the cell death markers for early apoptosis, late apoptosis and necrosis, and the involvement of the caspase signalling pathway. Alterations in calcium levels and reactive oxygen species were assessed due to their integral involvement in intracellular signalling. Subsequently, the endoplasmic reticulum (ER) and mitochondrial responses were investigated more closely. The extent of ER swelling, and the upregulation of proteins involved in the unfolded protein responses (UPR) were seen to vary according to cell line. The mitochondria were also shown to behave differently in response to the OphA in the different cell lines in terms of the change in membrane potential, the total area of mitochondria in the cell and the number of mitochondrial bifurcations. The data obtained in the present study indicate that the cancer cell lines tested are unable to successfully activate the ER stress/UPR responses, and that the mitochondria appear to be a central player in OphA-induced cancer cell death.
authors.affiliation: Department of Engineering Science, University of Oxford, Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Morrison
authors.affiliation: Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lodge
authors.affiliation: Dipartimento di Scienze Chimiche, Universita di Napoli Federico II Complesso Universitario Monte Sant'Angelo, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Experimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.affiliation: Department of Engineering Science, University of Oxford, Oxford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Townley
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009183:Mycotoxins / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D054830:Sesterterpenes / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D009183:Mycotoxins; D017382:Reactive Oxygen Species; D054830:Sesterterpenes; C040764:ophiobolin A; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002118:Calcium