Rapamycins: mechanism of action and cellular resistance.
TLDR
The conserved TOR signaling pathways, conceptual basis for tumor selectivity, and the mechanisms of resistance to this class of antitumor agent are reviewed.Abstract:
Rapamycins are macrocyclic lactones that possess immunosuppressive, antifungal and antitumor properties. The parent compound, rapamycin, is approved as an immunosup-pressive agent for preventing rejection in patients receiving organ transplantation. Two analogues, CCI-779 and RAD001 are currently being investigated as anticancer agents. Rapamycins first bind a cyclophilin FKBP12, and this complex binds and inhibits the function of mTOR (mammalian target of rapamycin) a serine/threonine (Ser/Thr) kinase with homology to phosphatidylinositol 3' kinase. Currently, as mTOR is the only identified target, this places rapamycins in a unique position of being the most selective kinase inhibitor known. Consequently these agents have been powerful tools in elucidating the role of mTOR in cellular growth, proliferation, survival and tumorigenesis. Increasing evidence suggests that mTOR acts as a central controller sensing cellular environment (nutritional status or mitogenic stimulation) and regulating translation initiation through the eukaryotic initiation factor 4E, and ribosomal p70 S6 kinase pathways. Here we review the conserved TOR signaling pathways, conceptual basis for tumor selectivity, and the mechanisms of resistance to this class of antitumor agent.read more
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Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.
Brinda Ravikumar,Coralie Vacher,Zdenek Berger,Janet E. Davies,Shouqing Luo,Lourdes Garcia Oroz,Francesco Scaravilli,Douglas F. Easton,Rainer Duden,Cahir J. O'Kane,David C. Rubinsztein +10 more
TL;DR: This work shows that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains, and provides proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
Journal ArticleDOI
The tor pathway: a target for cancer therapy
TL;DR: In addition to the role of rapamycin as an immune suppressant, emerging data indicate that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to TOR inhibition.
Journal ArticleDOI
Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition.
TL;DR: This study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor and shows that rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells.
Journal ArticleDOI
MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
Remi-Martin Laberge,Yu Sun,Arturo V. Orjalo,Christopher K. Patil,Adam Freund,Lili Zhou,Samuel C. Curran,Albert R. Davalos,Kathleen A. Wilson-Edell,Su Liu,Chandani Limbad,Marco Demaria,Patrick Wai-Lun Li,Gene B. Hubbard,Yuji Ikeno,Martin A. Javors,Pierre Yves Desprez,Christopher C. Benz,Pankaj Kapahi,Peter S. Nelson,Judith Campisi +20 more
TL;DR: It is shown that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells, which might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
Journal ArticleDOI
The TSC-mTOR Signaling Pathway Regulates the Innate Inflammatory Response
Thomas Weichhart,Giuseppina Costantino,Marko Poglitsch,Margit Rosner,Maximilian Zeyda,Karl M. Stuhlmeier,Thomas Kolbe,Thomas M. Stulnig,Walter H. Hörl,Markus Hengstschläger,Mathias Müller,Marcus D. Säemann +11 more
TL;DR: It is shown that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells, and protected genetically susceptible mice against lethal Listeria monocytogenes infection.
References
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Journal ArticleDOI
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