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

被引：167

作者：

Sarosiek, Kristopher A. ^{[1
,2
,13
]}

Fraser, Cameron ^{[1
]}

Muthalagu, Nathiya ^{[3
]}

Bhola, Patrick D. ^{[1
,2
]}

Chang, Weiting ^{[2
,4
,5
]}

McBrayer, Samuel K. ^{[1
,2
]}

Cantlon, Adam ^{[2
,4
,5
]}

Fisch, Sudeshna ^{[2
,4
,5
]}

Golomb-Mello, Gail ^{[6
]}

Ryan, Jeremy A. ^{[1
,2
]}

Deng, Jing ^{[1
,2
]}

Jian, Brian ^{[7
]}

Corbett, Chris ^{[8
]}

Goldenberg, Marti ^{[8
]}

Madsen, Joseph R. ^{[2
,8
]}

Liao, Ronglih ^{[2
,4
,5
]}

Walsh, Dominic ^{[2
,4
,5
]}

Sedivy, John ^{[6
]}

Murphy, Daniel J. ^{[3
,9
]}

Carrasco, Daniel Ruben ^{[1
,2
]}

Robinson, Shenandoah ^{[2
,8
]}

Moslehi, Javid ^{[10
,11
,12
]}

Letai, Anthony ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Mayer 430, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[4] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA

[6] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA

[7] Kaiser Permanente, Dept Neurosurg, Sacramento, CA 95815 USA

[8] Boston Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA

[9] Univ Glasgow, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland

[10] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA

[11] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Hematol Oncol, Nashville, TN 37232 USA

[12] Vanderbilt Univ, Dept Med, Sch Med, Cardiooncol Program,Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[13] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, John B Little Ctr Radiat Sci, Boston, MA 02115 USA

来源：

CANCER CELL | 2017年 / 31卷 / 01期

关键词：

CELL-DEATH; ALZHEIMERS-DISEASE; BRAIN MITOCHONDRIA; BCL-2; FAMILY; NEURAL CELL; BAX; EXPRESSION; BIM; PATHWAYS; THERAPY;

D O I：

10.1016/j.ccell.2016.11.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：142 / 156

页数：15

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