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CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance

Rui Liu1, Ming Fan1, Demet Candas1

  • 1Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.

Molecular Cancer Therapeutics
|July 5, 2015
PubMed

Insights

Tumor cells develop radiation resistance through increased SIRT3 expression and activity, driven by NF-κB and CDK1. Targeting SIRT3 phosphorylation could enhance radiotherapy effectiveness.

Area of Science:

  • Mitochondrial Biology
  • Cancer Research
  • Radiotherapy

Background:

  • Tumor adaptive resistance to radiation therapy limits cancer control.
  • Sirtuin 3 (SIRT3) regulates mitochondrial homeostasis and metabolism.
  • SIRT3 deacetylase activity is crucial for cellular functions.

Purpose of the Study:

  • Investigate the role of SIRT3 in adaptive radioresistance.
  • Elucidate the regulatory mechanisms of SIRT3 in response to radiation.
  • Evaluate SIRT3 as a potential target to overcome radioresistance.

Main Methods:

  • Analysis of SIRT3 expression in radiation-treated human tumor cells and xenografts.
  • Investigation of SIRT3 transcriptional regulation by NF-κB.
  • Assessment of SIRT3 posttranslational modification by cyclin B1-CDK1.
  • Functional studies using wild-type and mutant SIRT3 (Thr150Ala/Ser159Ala).

Main Results:

  • SIRT3 expression and activity are induced by radiation in various cancer cells.
  • NF-κB activates SIRT3 transcription; cyclin B1-CDK1 enhances SIRT3 activity via phosphorylation.
  • Mutant SIRT3 (Thr150Ala/Ser159Ala) impairs mitochondrial function and reduces radioresistance.
  • Tumors with mutant SIRT3 exhibit inhibited growth and increased sensitivity to irradiation.

Conclusions:

  • Enhanced SIRT3 transcription and mitochondrial posttranslational modifications contribute to adaptive radioresistance.
  • CDK1-mediated SIRT3 phosphorylation is a key mechanism in radioresistance.
  • Targeting CDK1-mediated SIRT3 phosphorylation may sensitize tumors to radiotherapy.

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