TY - JOUR
T1 - MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
AU - Laberge, Remi Martin
AU - Sun, Yu
AU - Orjalo, Arturo V.
AU - Patil, Christopher K.
AU - Freund, Adam
AU - Zhou, Lili
AU - Curran, Samuel C.
AU - Davalos, Albert R.
AU - Wilson-Edell, Kathleen A.
AU - Liu, Su
AU - Limbad, Chandani
AU - Demaria, Marco
AU - Li, Patrick
AU - Hubbard, Gene B.
AU - Ikeno, Yuji
AU - Javors, Martin
AU - Desprez, Pierre Yves
AU - Benz, Christopher C.
AU - Kapahi, Pankaj
AU - Nelson, Peter S.
AU - Campisi, Judith
N1 - Funding Information:
We thank A. Rogers, B. Kennedy, G. Lithgow, S. Melov and members of the Campisi laboratory (Buck Institute) for comments and discussions, I. Coleman for assistance with figure preparation and data analysis, and R. Strong (U Texas Health Science Center) for providing the rapamycin encapsulated chow. This work was supported by grants from the National Institutes of Health (NIH) AG045288 to R.-M.L., Hillblom Medical Foundation (CP), NIH T32 training grant AG000266-16 to K.A.W.-E., NIH grants CA143858, CA155679 and CA071468 to C.C.B., NIH grants AG032113 and AG025901 to P.K., DOD-PCRP grant PC111703 and National Natural Science Foundation of China 81472709 to Y.S., NIH grants CA164188, CA165573 and CA097186 and the Prostate Cancer Foundation to P.S.N., and NIH grants AG09909 and AG017242 to J.C. and AG041122 to J.C. and Y.I.
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/8/6
Y1 - 2015/8/6
N2 - 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-κB 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.
AB - 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-κB 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.
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U2 - 10.1038/ncb3195
DO - 10.1038/ncb3195
M3 - Article
C2 - 26147250
AN - SCOPUS:84938751873
VL - 17
SP - 1049
EP - 1061
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 8
ER -