Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia

被引：306

作者：

Cole, Alicia ^{[1
]}

Wang, Zezhou ^{[1
]}

Coyaud, Etienne ^{[1
]}

Voisin, Veronique ^{[2
]}

Gronda, Marcela ^{[1
]}

Jitkova, Yulia ^{[1
]}

Mattson, Rachel ^{[1
]}

Hurren, Rose ^{[1
]}

Babovic, Sonja ^{[3
,4
]}

Maclean, Neil ^{[1
]}

Restall, Ian ^{[1
]}

Wang, Xiaoming ^{[1
]}

Jeyaraju, Danny V. ^{[1
]}

Sukhai, Mahadeo A. ^{[1
]}

Prabha, Swayam ^{[1
]}

Bashir, Shaheena ^{[2
]}

Ramakrishnan, Ashwin ^{[1
]}

Leung, Elisa ^{[5
]}

Qia, Yi Hua ^{[6
]}

Zhang, Nianxian ^{[7
]}

Combes, Kevin R. ^{[6
]}

Ketela, Troy ^{[8
]}

Lin, Fengshu ^{[1
]}

Houry, Walid A. ^{[5
]}

Aman, Ahmed ^{[9
]}

Al-awar, Rima ^{[9
,10
]}

Zheng, Wei ^{[11
]}

Wienholds, Erno ^{[1
,12
]}

Xu, Chang Jiang ^{[2
]}

Dick, John ^{[1
,12
]}

Wang, Jean C. Y. ^{[1
,12
]}

Moffat, Jason ^{[8
]}

Minden, Mark D. ^{[1
,12
]}

Eaves, Connie J. ^{[3
,4
]}

Bader, Gary D. ^{[2
]}

Hao, Zhenyue ^{[1
]}

Kornblau, Steven M. ^{[6
]}

Raught, Brian ^{[1
]}

Schimmer, Aaron D. ^{[1
,12
]}

机构：

[1] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada

[2] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[3] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada

[4] Univ British Columbia, Vancouver, BC V5Z 1L3, Canada

[5] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

[6] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[8] Donnelly Ctr Cellular & Biomol Res, Dept Mol Genet, Toronto, ON M5S 3E1, Canada

[9] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3, Canada

[10] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[11] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA

[12] Univ Toronto, Dept Med, Toronto, ON M5G 2C4, Canada

来源：

CANCER CELL | 2015年 / 27卷 / 06期

基金：

加拿大健康研究院;

关键词：

ADVERSE PROGNOSTIC-FACTOR; HUMAN HOMOLOG; EXPRESSION; BORTEZOMIB; CARFILZOMIB; SOFTWARE; TARGETS;

D O I：

10.1016/j.ccell.2015.05.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

引用

页码：864 / 876

页数：13

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