We have demonstrated a reciprocal function for downregulation of AKT activation and inhibition of cell survival signaling by Smad 3. Moreover, we have shown that autocrine Smad 3 carries out an apoptotic function, in part, by repressing the oncogenic survival protein, survivin. Autocrine Smad 3 function appears? to involve attenuation of cell survival signaling. An important objective of the project is to determine the function of the Smad3/AKT node in response to cellular stresses such as growth factor and nutrient? deprivation as well as hypoxia. As malignant progression associated with loss of TGFp signaling occurs, the ability to respond to environmental stress is lot. In contrast, we have found that GFDS enhances the expression Smad 3 which transcriptionally represses survivin expression and at the same time reduces AKT activation as well as downstream activation of NFicB, another well known survival signaling mediator in cells with functional TGFp signaling. Thus, this control node appears to be an important means by which cells? communicate and react to the environment. As such, it would appear to be a ripe target for disruption during malignant progression. To learn more about how this stress response node controls death and survival we propose to utilize knockdown models described above that are specific for Smad2 and SmadS in Specific? Aim 1 to further test the hypothesis that Smad 3, but not Smad 2 is responsible for this mechanism of control by determining the roles that preformed cytoplasmic complexes containing SmadS bound to transcription factor complexes responsible for control of inhibition the cell cycle by TGFp play in carrying out the function? of the Smad3/AKT node activation. Finally, in Specific Aim 3 we will determine the relationship between the Smad3/AKT Specific Aim II will, therefore, also test the hypothesis that AKT promotes survivin expression through the phosphorylation of kBa and thus loss of Smad 3 not only released survivin from transcriptional? repression, but also increases its transcription through the restoration of AKT control node and malignant progression in vivo using orthotopic implantation and analysis of resulting changes in metastasis of colon cancer cells in athymic mice.
Aim 3 will utilize SmadS and Smad2 knockdown cells to determine whether the? SmadS/AKT node is linked to invasion and/or metastasis using orthotopic implantation models of colon? cancer.? ? SPECIFIC AIM 1: DETERMINE DIFFERENCES IN SIGNALING MECHANISMS BY AUTOCRINE VS? EXOGENOUS TGFB? ? SPECIFIC AIM 2: DETERMINE EFFECTS OF LOSS OF AUTOCRINE TGFp IN THE ESTABISHMENT? OF GROWTH ARREST AND CELL CYCLE RE-ENTRY? ? SPECIFIC AIM 3: DETERMINE EFFECTS OF LOSS OF AUTOCRINE TGFB ON APOPTOSIS?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37CA038173-22
Application #
7276687
Study Section
Special Emphasis Panel (NSS)
Program Officer
Blair, Donald G
Project Start
1986-07-01
Project End
2009-06-30
Budget Start
2007-09-20
Budget End
2008-06-30
Support Year
22
Fiscal Year
2007
Total Cost
$321,158
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Agarwal, E; Robb, C M; Smith, L M et al. (2017) Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis. Oncogene 36:3104-3118
Leiphrakpam, Premila D; Agarwal, Ekta; Mathiesen, Michelle et al. (2014) In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer. Oncol Rep 31:87-94
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Agarwal, Ekta; Brattain, Michael G; Chowdhury, Sanjib (2013) Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal 25:1711-9
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Sabbah, Dima A; Simms, Neka A; Wang, Wang et al. (2012) N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kýý). Bioorg Med Chem 20:7175-83
Sabbah, Dima A; Simms, Neka A; Brattain, Michael G et al. (2012) Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases. Bioorg Med Chem Lett 22:876-80
Simms, Neka A K; Rajput, Ashwani; Sharratt, Elizabeth A et al. (2012) Transforming growth factor-? suppresses metastasis in a subset of human colon carcinoma cells. BMC Cancer 12:221
Chowdhury, Sanjib; Howell, Gillian M; Teggart, Carol A et al. (2011) Histone deacetylase inhibitor belinostat represses survivin expression through reactivation of transforming growth factor beta (TGFbeta) receptor II leading to cancer cell death. J Biol Chem 286:30937-48

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