This revised grant application focuses on the role of the endogenous gaseous biological mediator hydrogen sulfide (H2S) in colorectal cancer. Based on multiple lines of novel data, we have developed the novel hypothesis that selective upregulation of cystathionine-?-synthase (CBS) and the subsequent production of H2S in colonic cancer cells serves as a pro-survival factor by stimulating tumor cell bioenergetics, growth, proliferation, migration and invasion. In order to explore this concept, we will pursue the following Aims: #1. To characterize the molecular mechanisms by which the CBS/H2S axis promotes tumor cell bioenergetics and tumor cell proliferation;#2. To determine the molecular mechanisms by which the CBS/H2S axis promotes tumor cell migration, invasion and metastasis;and #3. To evaluate the effect of the CBS inhibitor aminooxyacetic acid (AOAA) in human colorectal cancer, in a translationally relevant animal model utilizing patient-derived xenografts (PDTX) in combination with current clinical anticancer therapeutic agents. Taken together, the current project will utilize human colonic cancer tissues, human colonic cancer cell lines and tumor-bearing mice subjected to heterotopic transplantation of human colon cancer lines or patient-derived xenografts. To address the role of CBS, a combination of genetic (CBS silencing) and pharmacological (CBS inhibitors) approaches will be used. Outcome variables will include parameters of bioenergetics (oxidative phosphorylation, mitochondrial electron transport, glycolysis, GAPDH activity), cell proliferation, cell growth (including activation of pr-inflammatory/pro-growth kinase pathways), tumor cell migration, tumor cell invasion, angiogenesis and metastasis in vitro and in vivo. The role of sulfhydration (a specific H2S-mediated posttranslational protein modification) will be also explored on relevant protein targets (GAPDH, PTEN, PI3K). The final, translational aim will contain studies of potential therapeutic relevance, by testing the anticancer effect of CBS inhibitors, in summary, the current project entails a comprehensive approach to test the importance of CBS/H2S a novel pathway in colorectal cancer, and incorporates early translational work to explore its potential utility as a target for anticancer therapy.

Public Health Relevance

Although H2S, commonly referred to as swamp gas, seems like a very unlikely candidate for any role in human biology, recent data shows that both animal and human cells produce H2S, and use it for their own biological functions. However, tumor cells also produce large amounts of H2S gas, and use it to support their growth and expansion within a cancer patients'body. The proposed studies will lay the foundation of a radically new concept for cancer therapy by using a combined approach involving (1) human and mouse cancer cells grown in a dish, and (2) tumor-bearing mice that carry human or mouse tumors, to verify the theory that by blocking the tumor from overproducing H2S, the tumor will lose its fuel supply, stop growing, shrink, and be eliminated by the host's immunological defenses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA175803-01A1
Application #
8708260
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ault, Grace S
Project Start
2014-06-19
Project End
2019-05-31
Budget Start
2014-06-19
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$236,960
Indirect Cost
$83,959
Name
University of Texas Medical Br Galveston
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555