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

By Rémi-Martin Laberge, Yu Sun, Arturo V. Orjalo, C. Patil, Adam Freund, Lili Zhou, Samuel C. Curran, Albert R. Davalos, Kathleen A. Wilson-Edell, Su Liu and 11 more. Nature Cell Biology, 2015

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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.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/d66bd9a875b4eba93ff7bc408a878727e42dc58f

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Citations in the corpus

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases (2016, background): “However, the secretoma may provide indispensable cytokines for the cancer cells growth, thus promoting tumorigenesis in definite conditions, which are partly related to the cellular metabolic state [155].”
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “…(Freund et al., 2011), JAK2/STAT3 (Hubackova et al., 2010; Xu et al., 2015b), inflammasome (Acosta et al., 2013), mTOR (Herranz et al., 2015; Laberge et al., 2015), phosphoinositide-3-kinase (PI3K) pathway (Bent et al., 2016; Zhang et al., 2018), HSP90 (Di Martino et al., 2018), non-coding…”
JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age (2015, background): “Several drugs, including glucocorticoids (57), metformin (58), and rapamycin (59), have been found to inhibit the SASP.”
Senescence and the SASP: many therapeutic avenues (2020, background): “Given the intricate correlation between cGAS-STING, inflammation, senescence, and disease, several inhibitors of cGAS (Lama et al. 2019) and STING (Haag et al. 2018) have been developed.”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Most of the SASP components are regulated by the nuclear factor kappa light-chain–enhancer of activated B cells (NF- B), CCAAT/enhancer-binding protein beta (CEBP/ ) and by mTOR (5, 62, 132, 193, 196, 281).”
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse (2016, neutral): “Primer/probe sets for human and mouse p16, LmnB1, IL-1a, IL-6, Mmp-3, Mmp-9, Cxcl-1 were as previously reported (15, 32).”
Cellular Senescence: A Translational Perspective (2017, background): “…on the cell type from which senescent cells originated, how senescence was induced, hormonal milieu, and presence of drugs including glucocorticoids, rapamycin, metformin, or JAK1/2 inhibitors (Xu et al., 2015b, Wiley et al., 2016; Laberge et al., 2012; Moiseeva et al., 2013; Laberge et al., 2015).”
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Mechanisms and functions of cellular senescence. (2018, positive): “Indeed, the elimination of senescent cells reduces levels of proinflammatory cytokines such as IL-6, IL-1 α , and TNF-α in fat, kidneys, and skeletal muscle of aged mice (14, 15, 18).”