Colon cancer continues to be a leading cause of death in men and women. Other than surgical resection no other systemic or adjuvant therapy is available. Cumulative evidence in literature suggests that gastrins play a role in the proliferation of colon cancers. Colon cancer cells express the gastrin gene and a significant percent bind gastrins suggesting an autocrine role of gastrins.
In Aim 1 we will test the hypothesis that gastrin gene products function as autocrine growth factors for colon cancer cells by using antisense strategies. Specific antibodies will be used to assess the functional role of autocrine vs endocrine gastrins.
In Aim 2 we will test the hypothesis that src-like kinases mediate mitogenic/autocrine effects of gastrins. We will use microinjection technology to experimentally test the obligatory role of src-like kinases. Intestinal cells, overexpressing mutated src proteins will also be used. Recent studies suggest that novel receptors (GP-R), that bind both amidated and gly extended gastrins, mediate proliferative effects of gastrins on intestinal cells. Four other receptor-subtypes have been identified that mediate biological effects of gastrin on several target cells.
In Aim 3 we will examine the role of the various receptor-subtypes, including GP-R, in mediating mitogenic effects of gastrins. Since the novel GP-R have yet to be purified and cloned, we will purify GP-R for purposes of peptide sequencing and cDNA cloning in Aim 4. If studies under Aim 1 confirm a functional role of autocrine/endocrine gastrins in the growth and tumorigenicity of colon cancer cells then one can begin to develop treatment strategies that include reduction of gastrin gene expression. If studies under Aim 2 confirm a mediatory role of src PTKs then one can further develop strategies that block the signaling pathway. If we are successful in purifying the novel GP-R (and confirm its role in mediating the mitogenic effects of gastrins) then one can develop systemic strategies to block the receptor mediated effects in future funding periods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072992-03
Application #
2895800
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Spalholz, Barbara A
Project Start
1997-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Shen, Quiang; Singh, Pomila (2004) Identification of a novel SP3 binding site in the promoter of human IGFBP4 gene: role of SP3 and AP-1 in regulating promoter activity in CaCo2 cells. Oncogene 23:2454-64
Cobb, Stephanie; Wood, Thomas; Ceci, Jeffrey et al. (2004) Intestinal expression of mutant and wild-type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice. Cancer 100:1311-23
Rengifo-Cam, William; Singh, Pomila (2004) Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment. Curr Pharm Des 10:2345-58
Singh, P; Cobb, S; Rengifo-Cam, W et al. (2004) Locomotor activity and behavior of mutant mice deleted for gastrin gene expression. J Physiol Pharmacol 55:269-78
Brown, D; Yallampalli, U; Owlia, A et al. (2003) pp60c-Src Kinase mediates growth effects of the full-length precursor progastrin1-80 peptide on rat intestinal epithelial cells, in vitro. Endocrinology 144:201-11
Singh, P; Lu, X; Cobb, S et al. (2003) Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites. Am J Physiol Gastrointest Liver Physiol 284:G328-39
Cobb, Stephanie; Wood, Thomas; Tessarollo, Lino et al. (2002) Deletion of functional gastrin gene markedly increases colon carcinogenesis in response to azoxymethane in mice. Gastroenterology 123:516-30
Dai, B; Wu, H; Holthuizen, E et al. (2001) Identification of a novel cis element required for cell density-dependent down-regulation of insulin-like growth factor-2 P3 promoter activity in Caco2 cells. J Biol Chem 276:6937-44
Wu, H; Rao, G N; Dai, B et al. (2000) Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3. J Biol Chem 275:32491-8

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