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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,†,*  and 2,3
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 cancer; death receptor; caspase 8; Bcl2; apoptosome; XIAP; single cell analysis; Monte Carlo; computer simulation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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