Circadian regulation of mTOR by the ubiquitin pathway in renal cell carcinoma

Hiroyuki Okazaki, Naoya Matsunaga, Takashi Fujioka, Fumiyasu Okazaki, Yui Akagawa, Yuuya Tsurudome, Mayumi Ono, Michihiko Kuwano, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 tumorbearing 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.

Original languageEnglish
Pages (from-to)543-551
Number of pages9
JournalCancer Research
Volume74
Issue number2
DOIs
Publication statusPublished - Jan 15 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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