title: MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.
abstract: 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.
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Remi-Martin
authors.initials: RM
authors.lastname: Laberge
authors.affiliation: 1] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Key Lab of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Arturo V
authors.initials: AV
authors.lastname: Orjalo
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Patil
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Freund
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Curran
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: Davalos
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Wilson-Edell
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Chandani
authors.initials: C
authors.lastname: Limbad
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Li
authors.affiliation: 1] Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Gene B
authors.initials: GB
authors.lastname: Hubbard
authors.affiliation: 1] Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [3] Research Service, San Antonio, Texas 78229, USA [4] GRECC, Audie Murphy VA Hospital (STVHCS), San Antonio, Texas 78229, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Javors
authors.affiliation: 1] Buck Institute for Research on Aging, Novato, California 94945, USA [2] California Pacific Medical Center, Research Institute, San Francisco, California 94107, USA.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Benz
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kapahi
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D008942:Mitoxantrone / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; C508584:IL1A protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D008942:Mitoxantrone; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus