Abstract

One idea of personalized cancer therapy is to identify specific subgroups of cancer patients that will benefit from specific therapeutic strategies. Recently, the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research. This research proposal addresses an NCI emphasis: that is how do the proteins that direct life span, at least in some part, affect the molecular mechanisms of cancer development. In addition, can a greater understanding of the mechanisms that direct aging be used to enhance the prevention and/or treatment of cancer? In this regard, it is proposed that the CLOCK/NAD+/SIRT3 axis plays a role in the prevention of damage for IR the deletion of the genes in the axis in mice should result in the creation of new murine models for the investigation of human illness, including human malignancies, that have a strong genetic connection to aging or the genes in the CLOCK/NAD+/SIRT3 axis. In this regard, our preliminary results suggest that circadian CLOCK proteins coordinate mitochondrial metabolism, in part via the modulation of protein acetylation, including MnSOD, to metabolic and oxidative pathways with circadian rhythms. Based on our results, and those or others, it is hypothesized that the CLOCK/NAD+/SIRT3 signaling axis protects against IR-induced damage, cytotoxicity, genomic instability, and carcinogenesis, through the regulation of MnSOD mitochondrial detoxification activity via deacetylation of K68 and K122. In addition, it is proposed that this axis is a potentil molecular axis to sensitize tumor cells to cytotoxic strategies, including IR.

Public Health Relevance

This research proposal addresses the question of how does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In this regard, it is hypothesized that the CLOCK/NAD+/SIRT3 signaling axis protects against IR-induced damage, cytotoxicity, genomic instability, and carcinogenesis, through the regulation of MnSOD mitochondrial detoxification.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA152601-06A1
Application #
8914122
Study Section
Special Emphasis Panel (ZRG1-OTC-B (02))
Program Officer
Bernhard, Eric J
Project Start
2010-07-07
Project End
2020-03-31
Budget Start
2015-04-09
Budget End
2016-03-31
Support Year
6
Fiscal Year
2015
Total Cost
$362,734
Indirect Cost
$127,955

  Institution

Name
Northwestern University at Chicago
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926
Traver, Geri; Mont, Stacey; Gius, David et al. (2017) Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. Free Radic Biol Med 112:578-586
Jablonski, Renea P; Kim, Seok-Jo; Cheresh, Paul et al. (2017) SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 31:2520-2532
Yang, Xiaoyan; Park, Seong-Hoon; Chang, Hsiang-Chun et al. (2017) Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest 127:1505-1516
Liu, Guoxiang; Park, Seong-Hoon; Imbesi, Marta et al. (2017) Loss of NAD-Dependent Protein Deacetylase Sirtuin-2 Alters Mitochondrial Protein Acetylation and Dysregulates Mitophagy. Antioxid Redox Signal 26:849-863
Zou, Xianghui; Zhu, Yueming; Park, Seong-Hoon et al. (2017) SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth. Cancer Res 77:3990-3999
Zou, Xianghui; Santa-Maria, Cesar Augusto; O'Brien, Joseph et al. (2016) Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype. Antioxid Redox Signal 25:326-36
Song, Ha Yong; Biancucci, Marco; Kang, Hong-Jun et al. (2016) SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status. Oncotarget 7:80336-80349
Park, Seong-Hoon; Ozden, Ozkan; Liu, Guoxiang et al. (2016) SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumor Growth. Cancer Res 76:3802-12
Vidimar, Vania; Gius, David; Chakravarti, Debabrata et al. (2016) Dysfunctional MnSOD leads to redox dysregulation and activation of prosurvival AKT signaling in uterine leiomyomas. Sci Adv 2:e1601132

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