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Updated: May 5, 2026

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

Hiroyuki Okazaki1, Naoya Matsunaga, Takashi Fujioka

  • 1Authors' Affiliations: Departments of Pharmaceutics and Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Cancer Research
|November 21, 2013
PubMed

Insights

Circadian rhythms regulate mTOR activity in tumors. Timing mTOR inhibitor drugs to elevated mTOR periods improves survival in mice, revealing a new cancer treatment strategy.

Area of Science:

  • Chronobiology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Circadian clocks govern essential mammalian functions, including cell division and hormone secretion.
  • The mechanistic target of rapamycin (mTOR) pathway is crucial for cell growth and frequently dysregulated in cancer.
  • Understanding circadian regulation of mTOR may offer novel therapeutic strategies.

Purpose of the Study:

  • To investigate the impact of circadian control on mTOR activity in tumors.
  • To determine if optimizing the dosing schedule of an mTOR inhibitor can enhance its antitumor efficacy.
  • To elucidate the molecular mechanisms linking circadian rhythms to mTOR regulation.

Main Methods:

  • Analysis of circadian rhythms of mTOR protein and mRNA levels in RenCa tumor masses.
  • Identification of regulatory factors involved in mTOR oscillation.
  • Pharmacological intervention with an mTOR inhibitor (everolimus) based on circadian timing in tumor-bearing mice.

Main Results:

  • Phosphorylated mTOR exhibited a 24-hour rhythm in tumor masses, with total mTOR protein also showing circadian oscillation.
  • The study identified Fbxw7, a ubiquitination factor, as a regulator of mTOR, with its expression oscillating inversely to mTOR.
  • Fbxw7 transcription is regulated by the circadian protein D-site-binding protein.
  • Administering everolimus during peak mTOR activity significantly improved survival in tumor-bearing mice.

Conclusions:

  • Circadian clock systems actively regulate the oscillation of mTOR activity.
  • The circadian rhythm of mTOR influences the effectiveness of mTOR inhibitors in cancer treatment.
  • Optimizing drug delivery schedules based on circadian rhythms holds promise for improving cancer therapy outcomes.

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