Cells 2013, 2(2), 361-392; doi:10.3390/cells2020361
Article

Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells

1 Department of Chemistry, University of California Davis, Davis, CA 95776, USA 2 Genome Center, University of California Davis, Davis, CA 95776, USA 3 Department of Biomedical Engineering, University of California Davis, Davis, CA 95776, USA Other address: Indraprastha Institute of Information Technology, Delhi, Delhi 110020, India.
* Author to whom correspondence should be addressed.
Received: 13 March 2013; in revised form: 10 May 2013 / Accepted: 14 May 2013 / Published: 30 May 2013
(This article belongs to the Special Issue Apoptosis)
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Abstract: Apoptotic cell death is coordinated through two distinct (type 1 and type 2) intracellular signaling pathways. How the type 1/type 2 choice is made remains a central problem in the biology of apoptosis and has implications for apoptosis related diseases and therapy. We study the problem of type 1/type 2 choice in silico utilizing a kinetic Monte Carlo model of cell death signaling. Our results show that the type 1/type 2 choice is linked to deterministic versus stochastic cell death activation, elucidating a unique regulatory control of the apoptotic pathways. Consistent with previous findings, our results indicate that caspase 8 activation level is a key regulator of the choice between deterministic type 1 and stochastic type 2 pathways, irrespective of cell types. Expression levels of signaling molecules downstream also regulate the type 1/type 2 choice. A simplified model of DISC clustering elucidates the mechanism of increased active caspase 8 generation and type 1 activation in cancer cells having increased sensitivity to death receptor activation. We demonstrate that rapid deterministic activation of the type 1 pathway can selectively target such cancer cells, especially if XIAP is also inhibited; while inherent cell-to-cell variability would allow normal cells stay protected.
Keywords: cancer; death receptor; caspase 8; Bcl2; apoptosome; XIAP; single cell analysis; Monte Carlo; computer simulation

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MDPI and ACS Style

Raychaudhuri, S.; Raychaudhuri, S.C. Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells. Cells 2013, 2, 361-392.

AMA Style

Raychaudhuri S, Raychaudhuri SC. Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells. Cells. 2013; 2(2):361-392.

Chicago/Turabian Style

Raychaudhuri, Subhadip; Raychaudhuri, Somkanya C. 2013. "Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells." Cells 2, no. 2: 361-392.

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