One idea of personalized cancer therapy is to identify specific subgroup of cancer patients that will benefit from specific therapeutic strategy. 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 identified as the NCI's "Provocative Questions". This research proposal addresses one such question "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 addition, can the pathways that direct life span be used to identify potential molecular biomarkers and targets that can subsequently be used to identify specific groups of malignancies that will respond to targeted anticancer agents? This proposal clearly addresses this question in that we have previously shown that mice lacking mitochondrial Sirt3 gene develop estrogen receptor (ER) positive mammary tumors, a subtype of breast cancer predominantly observed in older women. Clinical data also suggest that there is a subgroup of ER positive luminal B human breast cancers that exhibit partial or complete loss of SIRT3 expression. In the last year the laboratory has made significant progress in delineating the underlying mechanistic relationship between reactive oxygen species (ROS) levels, HIF-1a signaling, and an in vivo phenotype permissive for breast carcinogenesis. Thus, it is proposed that there may be a specific subgroup of breast malignancies where loss of Sirt3 results in increased ROS and HIF1a that are early events in carcinogenesis and as such, agents that scavenge ROS molecules and/or inhibit HIF1a may prove to enhance cancer prevention or treatment. In this grant application we propose that mice lacking Sirt3 are a novel in vivo model in which to investigate the well established connection between decreased SIRT3 levels and ROS, HIF-1a, the Warburg effect, and breast malignancies. We hypothesize that agents thought to scavenge or decrease cellular ROS (O2-.) and/or inhibit HIF-1? activity will prevent tumors in Sirt3 knockout mice.

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, the Sirt3 knockout mouse is an in vivo murine model that genetically connects the sirtuin aging gene family, cellular metabolism, and mammary ductal cell tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168292-02
Application #
8549177
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (09))
Program Officer
Perloff, Marjorie
Project Start
2012-09-21
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$356,791
Indirect Cost
$125,858
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
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
Zhang, Hui; Head, PamelaSara E; Daddacha, Waaqo et al. (2016) ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA. Cell Rep 14:1435-47
Liu, Rui; Fan, Ming; Candas, Demet et al. (2015) CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance. Mol Cancer Ther 14:2090-102
Antic, Irena; Biancucci, Marco; Zhu, Yueming et al. (2015) Site-specific processing of Ras and Rap1 Switch I by a MARTX toxin effector domain. Nat Commun 6:7396
Agarwal, Shivangi; Zhu, Yeuming; Gius, David R et al. (2015) The Makes Caterpillars Floppy (MCF)-Like Domain of Vibrio vulnificus Induces Mitochondrion-Mediated Apoptosis. Infect Immun 83:4392-403
Lantier, Louise; Williams, Ashley S; Williams, Ian M et al. (2015) SIRT3 Is Crucial for Maintaining Skeletal Muscle Insulin Action and Protects Against Severe Insulin Resistance in High-Fat-Fed Mice. Diabetes 64:3081-92
Zhu, Yueming; Paul, Pritha; Lee, Sora et al. (2015) Antioxidant inhibition of steady-state reactive oxygen species and cell growth in neuroblastoma. Surgery 158:827-36
Pillai, Vinodkumar B; Samant, Sadhana; Sundaresan, Nagalingam R et al. (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 6:6656
Zhu, Yueming; Yan, Yufan; Principe, Daniel R et al. (2014) SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer Metab 2:15
Ozden, Ozkan; Park, Seong-Hoon; Wagner, Brett A et al. (2014) SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med 76:163-72

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