title: Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1.
abstract: DNA-damaging agents can induce premature senescence in cancer cells, which contributes to the static effects of cancer. However, senescent cancer cells may re-enter the cell cycle and lead to tumor relapse. Understanding the mechanisms that control the viability of senescent cells may be helpful in eliminating these cells before they can regrow. Treating human squamous cell carcinoma (SCC) cells with the anti-cancer compounds, resveratrol and doxorubicin, triggered p53-independent premature senescence by invoking oxidative stress-mediated DNA damage. This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1. SIRT1 phosphorylation caused concomitant increases in p65/RelA NF-κB acetylation and the expression of an anti-apoptotic Bfl-1/A1. SIRT1 physically interacts with the mTOR-Raptor complex, and a single amino acid substitution in the TOS (TOR signaling) motif in the SIRT1 prevented Ser-47 phosphorylation and Bfl-1/A1 induction. The pharmacologic and genetic inhibition of mTOR, unphosphorylatable S47A, or F474A TOS mutants restored SIRT1 deacetylase activity, blocked Bfl-1/A1 induction, and sensitized prematurely senescent SCC cells for apoptosis. We further show that the treatment of UVB-induced SCCs with doxorubicin transiently stabilized tumor growth but was followed by tumor regrowth upon drug removal in p53(+/-)/SKH-1 mice. The subsequent treatment of stabilized SCCs with rapamycin decreased tumor size and induced caspase-3 activation. These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent SCC cells via Bfl-1/A1 in the absence of functional p53.
authors.affiliation: Department of Dermatology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Back
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Rezvani
authors.forename: Yucui
authors.initials: Y
authors.lastname: Zhu
authors.forename: Véronique
authors.initials: V
authors.lastname: Guyonnet-Duperat
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.forename: Desiree
authors.initials: D
authors.lastname: Ratner
authors.forename: Arianna L
authors.initials: AL
authors.lastname: Kim
mesh_terms: D000107:Acetylation / Q000187:drug effects / Q000528:radiation effects; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D016922:Cellular Senescence; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D020125:Mutation, Missense; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; C096816:BCL2-related protein A1; D002352:Carrier Proteins; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; C498143:RELA protein, human; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C498144:Rela protein, mouse; C540162:Rptor protein, mouse; C495901:TP53 protein, human; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1