MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation

被引：950

作者：

Laberge, Remi-Martin ^{[1
]}

Sun, Yu ^{[2
,3
]}

Orjalo, Arturo V. ^{[1
]}

Patil, Christopher K. ^{[1
]}

Freund, Adam ^{[1
]}

Zhou, Lili ^{[1
]}

Curran, Samuel C. ^{[1
]}

Davalos, Albert R. ^{[1
]}

Wilson-Edell, Kathleen A. ^{[1
]}

Liu, Su ^{[1
]}

Limbad, Chandani ^{[1
]}

Demaria, Marco ^{[1
]}

Li, Patrick ^{[1
]}

Hubbard, Gene B. ^{[4
,5
]}

Ikeno, Yuji ^{[4
,5
,6
,7
]}

Javors, Martin ^{[8
]}

Desprez, Pierre-Yves ^{[1
,9
]}

Benz, Christopher C. ^{[1
]}

Kapahi, Pankaj ^{[1
]}

Nelson, Peter S. ^{[2
]}

Campisi, Judith ^{[1
]}

机构：

[1] Buck Inst Res Aging, Novato, CA 94945 USA

[2] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA

[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China

[4] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA

[5] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA

[6] Res Serv, San Antonio, TX 78229 USA

[7] Audio Murphy VA Hosp STVHCS, GRECC, San Antonio, TX 78229 USA

[8] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA

[9] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA

来源：

NATURE CELL BIOLOGY | 2015年 / 17卷 / 08期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

CELLULAR SENESCENCE; TUMOR-CELLS; DNA-DAMAGE; HUMAN FIBROBLASTS; GROWTH ARREST; CANCER; P53; INFLAMMATION; EXPRESSION; PATHWAY;

D O I：

10.1038/ncb3195

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-kappa B transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.

引用

页码：1049 / U416

页数：32

共 71 条

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