The nutritionally essential element Se is also chemopreventive against prostate, lung, and several other leading human cancers when administered at supranutritional levels. The complex biochemical mechanism(s) underlying the anticancer action of Se compounds are not understood but they depend on Se metabolism in conjunction with multiple steps of redox regulation and antioxidation. Previously impractical, such complexity can now be explored by combining the power of new molecular profiling tools. With metabolomics-edited transcriptomic analysis (META) to guide targeted proteomics, we have recently discovered key changes in metabolic and regulatory pathways in Se-exposed lung cancer cells that control cell growth and migration. These preliminary results led to our current hypothesis: (a) the primary site(s) of Se action involve covalent modification(s) of key redox-sensitive proteins including thioredoxin reductase (TrxR) and NF:B;(b) their resultant dysfunctions lead to cell death and anti-metastasis. Here, we propose to expand the approach to human Small Cell Lung Cancer cells with different metastatic potential for in vivo validation in a RAG1 null mice model.
Our specific aims are:
Aim 1 : To define and correlate the biochemical pathway profiles with phenotypic changes of selected human lung cancer cell lines in response to treatments of different Se forms. The metabolomics data will be used to discern metabolic pathways related to growth, apoptosis, and metastatic potential (motility, chemotaxis, and adhesion);
Aim 2 : To acquire global and focused gene expression profiles of the treated cells for correlation to the metabolic profiles obtained from Aim 1. Using META, gene expression profiles will be prioritized based on actual metabolic changes from Aim 1 to reveal Se action on regulatory pathways and key target proteins;
Aim 3 : To verify key working hypotheses in cell systems using a combination of immunochemical and proteomics analyses. [Potential key protein targets, TrxR, NF:B, and IKK2] will be verified by relating their function to the modification state;
Aim 4 : To validate in vivo Se action on lung cancer cell metastasis in a RAG null mouse model. Emphasis will be on metastasis involving the chemokine SDF-1 and its receptor CXCR4, which is regulated by the NF:B-TrxR pathway. Altered metastasis and molecular signature of target mice tissues and blood in response to Se treatments will be related to the cell-based molecular signatures from Aims 1-3 for in vivo validation and for connection to ongoing human patient studies. This work is expected to accelerate the development of mechanistic biomarkers for lung cancer chemoprevention, tumor diagnostics, and anticancer efficacy.

Public Health Relevance

The nutritionally essential element Selenium (Se) has been shown to have anti-cancer properties against prostate, lung and other cancers at supranutritional levels. The exact nature of this activity is presently unknown, but is related to the metabolism of selenium and how it reduces the ability of cancer cells to survive oxidative damages generated by their overactive metabolism. Here we propose to use state-of-the-science """"""""metabolomic"""""""" plus other """"""""'omics"""""""" tools to determine the biochemical basis of Se action in lung cancers using cell cultures and mouse models. This work is expected to accelerate the development of more sensitive diagnostics for lung cancer chemoprevention, tumor detection, and anticancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118434-04
Application #
8109937
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$297,887
Indirect Cost
Name
University of Louisville
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Higashi, Richard M; Fan, Teresa W-M; Lorkiewicz, Pawel K et al. (2014) Stable isotope-labeled tracers for metabolic pathway elucidation by GC-MS and FT-MS. Methods Mol Biol 1198:147-67
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Yuneva, Mariia O; Fan, Teresa W M; Allen, Thaddeus D et al. (2012) The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab 15:157-70
Fan, Teresa W-M; Lorkiewicz, Pawel K; Sellers, Katherine et al. (2012) Stable isotope-resolved metabolomics and applications for drug development. Pharmacol Ther 133:366-91

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