title: Systems analysis of cancer cell heterogeneity in caspase-dependent apoptosis subsequent to mitochondrial outer membrane permeabilization.
abstract: Deregulation of apoptosis is a hallmark of carcinogenesis. We here combine live cell imaging and systems modeling to investigate caspase-dependent apoptosis execution subsequent to mitochondrial outer membrane permeabilization (MOMP) in several cancer cell lines. We demonstrate that, although most cell lines that underwent MOMP also showed robust and fast activation of executioner caspases and apoptosis, the colorectal cancer cell lines LoVo and HCT-116 Smac(-/-), similar to X-linked inhibitor of apoptosis protein (XIAP)-overexpressing HeLa (HeLa XIAP(Adv)) cells, only showed delayed and often no caspase activation, suggesting apoptosis impairment subsequent to MOMP. Employing APOPTO-CELL, a recently established model of apoptosis subsequent to MOMP, this impairment could be understood by studying the systemic interaction of five proteins that are present in the apoptosis pathway subsequent to MOMP. Using APOPTO-CELL as a tool to study detailed molecular mechanisms during apoptosis execution in individual cell lines, we demonstrate that caspase-9 was the most important regulator in DLD-1, HCT-116, and HeLa cells and identified additional cell line-specific co-regulators. Developing and applying a computational workflow for parameter screening, systems modeling identified that apoptosis execution kinetics are more robust against changes in reaction kinetics in HCT-116 and HeLa than in DLD-1 cells. Our systems modeling study is the first to draw attention to the variability in cell specific protein levels and reaction rates and to the emergent effects of such variability on the efficiency of apoptosis execution and on apoptosis impairment subsequent to MOMP.
authors.affiliation: Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Schmid
authors.forename: Heiko
authors.initials: H
authors.lastname: Dussmann
authors.forename: Gerhardt J
authors.initials: GJ
authors.lastname: Boukes
authors.forename: Lorna
authors.initials: L
authors.lastname: Flanagan
authors.forename: Andreas U
authors.initials: AU
authors.lastname: Lindner
authors.forename: Carla L
authors.initials: CL
authors.lastname: O'Connor
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Huber
mesh_terms: D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008853:Microscopy / Q000379:methods; D051336:Mitochondrial Membranes / Q000201:enzymology*; D015233:Models, Statistical; D009010:Monte Carlo Method; D009369:Neoplasms / Q000378:metabolism*; D011379:Prognosis; D013379:Substrate Specificity; D013597:Systems Analysis; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D053453:Caspase 9; D020169:Caspases