Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics

Sarosiek, K. A. et al. (2017) Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell, 31(1), pp. 142-156. (doi: 10.1016/j.ccell.2016.11.011) (PMID:28017613) (PMCID:PMC5363285)

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Abstract

It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Murphy, Professor Daniel
Authors: Sarosiek, K. A., Fraser, C., Muthalagu, N., Bhola, P. D., Chang, W., McBrayer, S. K., Cantlon, A., Fisch, S., Golomb-Mello, G., Ryan, J. A., Deng, J., Jian, B., Corbett, C., Goldenberg, M., Madsen, J. R., Liao, R., Walsh, D., Sedivy, J., Murphy, D. J., Carrasco, D. R., Robinson, S., Moslehi, J., and Letai, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Cell
Publisher:Elsevier (Cell Press)
ISSN:1535-6108
ISSN (Online):1878-3686
Published Online:22 December 2016
Copyright Holders:Copyright © 2017 Elsevier
First Published:First published in Cancer Cell 31(1):142-156
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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