title: CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance.
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/Ser159Ala-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.
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Demet
authors.initials: D
authors.lastname: Candas
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Lili
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Angela
authors.initials: A
authors.lastname: Eldridge
authors.affiliation: Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, California.
authors.forename: June X
authors.initials: JX
authors.lastname: Zou
authors.affiliation: Center for Biophotonics Science and Technology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Tieqiao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Shuaib
authors.initials: S
authors.lastname: Juma
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California. NCI-designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Julian
authors.initials: J
authors.lastname: Perks
authors.affiliation: Center for Molecular Imaging, Central South University, Changsha, Hunan, China.
authors.forename: Lun-Quan
authors.initials: LQ
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California. NCI-designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Andrew T M
authors.initials: AT
authors.lastname: Vaughan
authors.affiliation: Department of Toxicology, Fourth Military Medical University, Xian, Shaanxi, China.
authors.forename: Chun-Xu
authors.initials: CX
authors.lastname: Hai
authors.affiliation: Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: David R
authors.initials: DR
authors.lastname: Gius
authors.affiliation: Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California. NCI-designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California. jijli@ucdavis.edu.
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D010766:Phosphorylation; D011836:Radiation Tolerance / Q000235:genetics*; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D024101:Mitochondrial Proteins; D016328:NF-kappa B; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D056566:Sirtuin 3