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Cancer Res ; 74(2): 543-51, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24253377

RESUMO

Circadian clock systems regulate many biologic functions, including cell division and hormone secretion in mammals. In this study, we explored the effects of circadian control on the pivot cell growth regulatory mTOR, the activity of which is deregulated in tumor cells compared with normal cells. Specifically, we investigated whether the antitumor effect of an mTOR inhibitor could be improved by changing its dosing schedule in RenCa tumor-bearing mice. Active, phosphorylated mTOR displayed a 24-hour rhythm, and levels of total mTOR protein (but not mRNA) also showed a circadian rhythm in RenCa tumor masses. Through investigations of the oscillation mechanism for mTOR expression, we identified the ubiquitination factor Fbxw7 as an mTOR regulator that oscillated in its expression in a manner opposite from mTOR. Fbxw7 transcription was regulated by the circadian regulator D-site-binding protein. Notably, administration of the mTOR inhibitor everolimus during periods of elevated mTOR improved survival in tumor-bearing mice. Our findings demonstrate that the circadian oscillation of mTOR activity is regulated by circadian clock systems, which influence the antitumor effect of mTOR inhibitors.


Assuntos
Carcinoma de Células Renais/metabolismo , Ritmo Circadiano , Neoplasias Renais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Everolimo , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Transplante de Neoplasias , Oscilometria , Transdução de Sinais , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Fatores de Tempo , Ubiquitina-Proteína Ligases/metabolismo
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