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

Cancer Res. 2014 Jan 15;74(2):543-51. doi: 10.1158/0008-5472.CAN-12-3241. Epub 2013 Nov 19.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Circadian Rhythm*
  • Everolimus
  • F-Box Proteins / metabolism
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Immunosuppressive Agents / pharmacology
  • Kidney Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NIH 3T3 Cells
  • Neoplasm Transplantation
  • Oscillometry
  • Signal Transduction
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Ubiquitin / chemistry*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • Immunosuppressive Agents
  • Ubiquitin
  • Everolimus
  • Ubiquitin-Protein Ligases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus