MTOR Regulates the Pro-Tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation

Nat Cell Biol. 2015 Aug;17(8):1049-61. doi: 10.1038/ncb3195. Epub 2015 Jul 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammation Mediators / metabolism
  • Interleukin-1alpha / genetics
  • Interleukin-1alpha / metabolism*
  • Interleukin-6 / metabolism
  • Male
  • Mice, SCID
  • Mitoxantrone / pharmacology
  • NF-kappa B / metabolism
  • Phenotype
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA Interference
  • RNA, Messenger / metabolism
  • Sirolimus / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Burden
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • IL1A protein, human
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-1alpha
  • Interleukin-6
  • NF-kappa B
  • RNA, Messenger
  • Mitoxantrone
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus