@article{9879cbf17bd048989d94f034347b28a9,
title = "Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics",
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.",
keywords = "apoptosis, c-Myc, cardiotoxicity, cell death regulation, chemosensitivity, neurotoxicity, pediatric cancer, radiosensitivity, side effects of chemotherapy, side effects of radiation therapy",
author = "Sarosiek, {Kristopher A.} and Cameron Fraser and Nathiya Muthalagu and Bhola, {Patrick D.} and Weiting Chang and McBrayer, {Samuel K.} and Adam Cantlon and Sudeshna Fisch and Gail Golomb-Mello and Ryan, {Jeremy A.} and Jing Deng and Brian Jian and Chris Corbett and Marti Goldenberg and Madsen, {Joseph R.} and Ronglih Liao and Dominic Walsh and John Sedivy and Murphy, {Daniel J.} and Carrasco, {Daniel Ruben} and Shenandoah Robinson and Javid Moslehi and Anthony Letai",
note = "Funding Information: We thank J. Sims, P. Sorger, X. Chi, L. Walensky, D. Andrews, C. Unitt, T. Bowman, O. Pozdnyakova, and S. White for providing assistance and B. Mar, J. Montero, G. Joshi, and L. Boise for critical review of our manuscript. We gratefully acknowledge funding from the American Cancer Society Postdoctoral Fellowship 121360-PF-11-256-01-TBG (K.A.S.), Alex's Lemonade Stand Foundation for Childhood Cancers Young Investigator Award (K.A.S.), as well as NIH grants K99CA188679 (K.A.S.), RO1CA129974 (A.L.), and P01CA066996 (A.L.). A.L. was a Leukemia and Lymphoma Society Scholar. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jan,
day = "9",
doi = "10.1016/j.ccell.2016.11.011",
language = "English (US)",
volume = "31",
pages = "142--156",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}