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.
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.
|Untereiner, Ashley A; Pavlidou, Athanasia; Druzhyna, Nadiya et al. (2018) Drug resistance induces the upregulation of H2S-producing enzymes in HCT116 colon cancer cells. Biochem Pharmacol 149:174-185|
|Szabo, Csaba (2018) A timeline of hydrogen sulfide (H2S) research: From environmental toxin to biological mediator. Biochem Pharmacol 149:5-19|
|Oláh, Gabor; Módis, Katalin; Törö, Gabor et al. (2018) Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation. Biochem Pharmacol 149:186-204|
|Phillips, Ches'Nique M; Zatarain, John R; Nicholls, Michael E et al. (2017) Upregulation of Cystathionine-?-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis. Cancer Res 77:5741-5754|
|Thanki, Ketan; Nicholls, Michael E; Gajjar, Aakash et al. (2017) Consensus Molecular Subtypes of Colorectal Cancer and their Clinical Implications. Int Biol Biomed J 3:105-111|
|Untereiner, Ashley A; Oláh, Gabor; Módis, Katalin et al. (2017) H2S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates cellular bioenergetics in HCT116 colon cancer cells. Biochem Pharmacol 136:86-98|
|Szabo, Csaba; Papapetropoulos, Andreas (2017) International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharmacol Rev 69:497-564|
|Druzhyna, Nadiya; Szczesny, Bartosz; Olah, Gabor et al. (2016) Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine ?-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon Pharmacol Res 113:18-37|
|Szabo, Csaba (2016) Gasotransmitters in cancer: from pathophysiology to experimental therapy. Nat Rev Drug Discov 15:185-203|
|Katsouda, Antonia; Bibli, Sofia-Iris; Pyriochou, Anastasia et al. (2016) Regulation and role of endogenously produced hydrogen sulfide in angiogenesis. Pharmacol Res 113:175-185|
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