CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance

Rui Liu, Ming Fan, Demet Candas, Lili Qin, Xiaodi Zhang, Angela Eldridge, June X. Zou, Tieqiao Zhang, Shuaib Juma, Cuihong Jin, Robert F. Li, Julian Perks, Lun Quan Sun, Andrew T.M. Vaughan, Chun Xu Hai, David R. Gius, Jian Jian Li*

*Corresponding author for this work

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Tumor adaptive resistance to therapeutic radiation remains a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors, including colon cancer HCT-116, glioblastoma U87, and breast cancer MDA-MB231 cells. SIRT3 transcriptional activation is due to SIRT3 promoter activation controlled by the stress transcription factor NF-κB. Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. Cells expressing Thr150Ala/Ser159Ala-mutant SIRT3 show a reduction in mitochondrial protein lysine deacetylation, Δψm, MnSOD activity, and mitochondrial ATP generation. The clonogenicity of Thr150Ala/Ser159Ala-mutant transfectants is lower and significantly decreased under radiation. Tumors harboring Thr150Ala/Ser159-Ala-mutant SIRT3 show inhibited growth and increased sensitivity to in vivo local irradiation. These results demonstrate that enhanced SIRT3 transcription and posttranslational modifications in mitochondria contribute to adaptive radioresistance in tumor cells. CDK1-mediated SIRT3 phosphorylation is a potential effective target to sensitize tumor cells to radiotherapy.

Original languageEnglish (US)
Pages (from-to)2090-2102
Number of pages13
JournalMolecular cancer therapeutics
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance'. Together they form a unique fingerprint.

  • Cite this

    Liu, R., Fan, M., Candas, D., Qin, L., Zhang, X., Eldridge, A., Zou, J. X., Zhang, T., Juma, S., Jin, C., Li, R. F., Perks, J., Sun, L. Q., Vaughan, A. T. M., Hai, C. X., Gius, D. R., & Li, J. J. (2015). CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance. Molecular cancer therapeutics, 14(9), 2090-2102. https://doi.org/10.1158/1535-7163.MCT-15-0017