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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 Dec 27

PMID 28017613

Citations 132

Authors

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 Carrasco

Shenandoah Robinson

Javid Moslehi

Anthony Letai

Affiliations

Soon will be listed here.

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.

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