MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
Authors: Remi-Martin Laberge
Samuel C Curran
Patrick Li
Christopher C Benz
Judith Campisi
Arturo V Orjalo
Marco Demaria
Chandani Limbad
Yu Sun
Adam Freund
Yuji Ikeno
Pierre-Yves Desprez
Su Liu
Peter S Nelson
Martin Javors
Albert R Davalos
Lili Zhou
Kathleen A Wilson-Edell
Gene B Hubbard
Christopher K Patil
Pankaj Kapahi
Journal: Nature Cell Biology (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: TOR kinase; longevity; rapamycin; TORC1 complex; translation
Affiliations: Buck Institute for Research on Aging, Novato, California 94945, USA., 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., 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., 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., Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA., 1] Buck Institute for Research on Aging, Novato, California 94945, USA [2] California Pacific Medical Center, Research Institute, San Francisco, California 94107, USA., Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

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. 

Retracted: No

PubPeer comments:
 Fig. 12.  Fluorescence micrographs of cow- and goat-ear pinna skin and rat skin treated with the formulation 5-FU-S (A) 5-FU-NE (B) 5-FU-NE-Gel (C). Different type of formulations labelled with hydrophilic fluorescence probe (6-carboxyfluorescein) to mark the penetration of the 5-FU to deep skin strata. ![file] Here, color-reversed, rotated through 90 deg. and two of the panels stretched horizontally. ![file] Please compare with Fig 10 from [Ahmad et al (2019)] , showing  Histopathology of skin at day 12 stained with H E; a control group animals showing, early epithelization, and granulation tissue and abundance of mononuclear infammatory cells (u03b1); b pure eucalyptus oil-treated rats showing healed skin structures with wellformed, near to normal epidermis, restoration of adnexa (u03b2), and extensive fbrosis and collagen tissue within the dermis (arrow) . ![file] , 
 Part of figure 4. How to explain the indicated phenomenon? https: imgur.com a ZOJpn54 , 
 Clockwise here from upper left: - Fig 7A from [Ahmad et al (2018)] .  The cumulative percentage release of Eugenol from EUG-NE as compared to pure Eugenol (reproduced as Fig. 5 in [Ahmad et al (2019)] ,  The cumulative percentage release of Eugenol from EUG ). - Fig. 2a from [Ahmad et al (2018b)] .  In vitro release profile of EUG-solution, EUG-loaded-PCL-NPs and CS-coated-EUG-loaded-PCL-NPs performed by using dialysis bag method, revealing sustained release pattern of EUG-loaded-PCL-NPs and CS-coated-EUG-loaded-PCL-NPs . - Fig. 5A from [Ahmad et al (2019a)] .  In vitro release profile of DAUNu2013S, DAUNu2013loadedu2013PLGAu2013NPs and CSu2013DAUNu2013PLGAu2013NPs performed by using dialysis bag method, revealing sustained release pattern of DAUNu2013PLGAu2013NPs, and CSu2013DAUNu2013PLGAu2013NPs . - Fig. (5)A from [Ahmad et al (2019b)] .  In vitro release profile of GRA-solution, GRA-loaded-PCL-NPs and CS-coated-GRA-loaded-PCL-NPs performed by using dialysis bag method, revealing sustained release pattern of GRA-loaded-PCL-NPs and CS-coated-GRA-loaded-PCL-NPs . - Fig 6a from [Ahmad et al (2019c)] .  The cumulative percentage release of curcumin from Cur-SNEDDS as compared to pure curcumin. - Fig 5A from [Ahmad et al (2020)] .  In vitro release profile of CTH-S, CTHu2013loadedu2013PLGAu2013NPs and Chitosan-coated-CTHu2013loadedu2013PLGAu2013NPs performed by using dialysis bag method, revealing sustained release pattern of CTHu2013loadedu2013PLGAu2013NPs and Chitosan-coated- CTHu2013loadedu2013PLGAu2013NPs (Temp was set at 37u202fu00b0C, meanu202fu00b1u202fSD, nu202f=u202f3) at pH 7.4 (reproduced as Fig 8A in [Ahmad et al (2020a)] ). - **Fig 6 from [Ahmad et al (2020b)] **,  the %age-cumulative-release of 5-FU from 5-FU-NE and 5-FU-NE-Gel when it compared with pure 5-FU-S . - Fig. 5a from [Ahmad et al (2020c)] .  In vitro release profile of THQ-S, and THQ-loaded-PLGA-NPs performed by using dialysis bag method, revealing sustained release pattern of THQ-PLGA-NPs . ![file] All 8 superimposed: ![file] Are there any nanopreparations with **different** pharmacokinetics? I am also impressed by the similarity of the release profiles of pure Eugenol, Daunorubicin, Glycyrrhizic Acid, curcumin, catechin, 5-FU and Thymoquinone, despite their different solubilities, etc.. ,