Type

Journal Article

Authors

Heinrich J Huber
Jochen H M Prehn
Markus Rehm
Carla L O'Connor
Andreas U Lindner
Lorna Flanagan
Gerhardt J Boukes
Heiko Düssmann
Jasmin Schmid

Subjects

Biochemistry

Topics
neoplasms x linked inhibitor of apoptosis protein substrate specificity cell line caspase 9 caspases humans metabolism enzymologic gene expression regulation hela cells enzymology neoplastic physics cell line tumor tumor systems analysis microscopy physiology kinetics mitochondrial membranes xiap protein human gene expression regulation enzymologic models statistical fluorescence resonance energy transfer statistical prognosis gene expression regulation neoplastic monte carlo method apoptosis

Systems analysis of cancer cell heterogeneity in caspase-dependent apoptosis subsequent to mitochondrial outer membrane permeabilization. (2012)

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.
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Full list of authors on original publication

Heinrich J Huber, Jochen H M Prehn, Markus Rehm, Carla L O'Connor, Andreas U Lindner, Lorna Flanagan, Gerhardt J Boukes, Heiko Düssmann, Jasmin Schmid

Experts in our system

1
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
2
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
3
Markus Rehm
Royal College of Surgeons in Ireland
Total Publications: 55
 
4
Carla L O'Connor
Royal College of Surgeons in Ireland
Total Publications: 3
 
5
Andreas U Lindner
Royal College of Surgeons in Ireland
Total Publications: 13
 
6
Lorna Flanagan
Royal College of Surgeons in Ireland
Total Publications: 23
 
7
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45
 
8
Jasmin Schmid
Royal College of Surgeons in Ireland
Total Publications: 13