Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4E

被引：389

作者：

Hsieh, Andrew C. ^{[1
,2
,3
]}

Costa, Maria ^{[1
,2
]}

Zollo, Ornella ^{[1
,2
]}

Davis, Cole ^{[1
,2
]}

Feldman, Morris E. ^{[4
]}

Testa, Joseph R. ^{[5
]}

Meyuhas, Oded ^{[6
]}

Shokat, Kevan M. ^{[4
]}

Ruggero, Davide ^{[1
,2
]}

机构：

[1] Univ Calif San Francisco, Sch Med, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Urol, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, Howard Hughes Med Inst, San Francisco, CA 94158 USA

[5] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA

[6] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91120 Jerusalem, Israel

来源：

CANCER CELL | 2010年 / 17卷 / 03期

基金：

美国国家卫生研究院;

关键词：

T-CELL DEVELOPMENT; MESSENGER-RNA TRANSLATION; RPS6; PHOSPHORYLATION; SIGNALING PATHWAY; PHAS-I; AKT; RAPAMYCIN; SURVIVAL; INITIATION; MINUTE;

D O I：

10.1016/j.ccr.2010.01.021

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers.

引用

页码：249 / 261

页数：13