Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics

Kristopher A. Sarosiek, Cameron Fraser, Nathiya Muthalagu, Patrick D. Bhola, Weiting Chang, Samuel K. McBrayer, Adam Cantlon, Sudeshna Fisch, Gail Golomb-Mello, Jeremy A. Ryan, Jing Deng, Brian Jian, Chris Corbett, Marti Goldenberg, Joseph R. Madsen, Ronglih Liao, Dominic Walsh, John Sedivy, Daniel J. Murphy, Daniel Ruben CarrascoShenandoah Robinson, Javid Moslehi, Anthony Letai

Research output: Contribution to journalArticle

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)142-156
Number of pages15
JournalCancer Cell
Volume31
Issue number1
DOIs
StatePublished - Jan 9 2017

Keywords

  • apoptosis
  • c-Myc
  • cardiotoxicity
  • cell death regulation
  • chemosensitivity
  • neurotoxicity
  • pediatric cancer
  • radiosensitivity
  • side effects of chemotherapy
  • side effects of radiation therapy

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    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., ... Letai, A. (2017). Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell, 31(1), 142-156. https://doi.org/10.1016/j.ccell.2016.11.011