The theme of this project has been the role of TGF-beta in the regulation of the biological behavior of colon cancer cells. The basic hypothesis of the last cycle of the project was that loss of autocrine negative TGF-beta was a significant determinant of malignant progression. During the last cycle of the project this hypothesis was confirmed by showing (1) repression of autocrine TGF-beta rather than loss of response to exogenous TGF-beta leads to malignant progression in vitro and in vivo, (2) an important mechanism of loss of autocrine TGF-beta was determined to be loss of the type II TGF-beta receptor (designated RII) by mutation in cell lines and primary tissues and (3) reconstitution of autocrine TGF-beta activity by RII expression reverses malignancy. Mutational inactivation of RII was found in colon cancer patients and cell lines with DNA repair defects leading to microsatellite instability (designated RER+). It is important to determine whether TGF-beta receptor expression is also defective in non-RER disease. Preliminary evidence has identified a subset of non-RER cell lines and tumors which shows a lack of RII expression while a second set shows reduced expression of RI expression which results in the elimination of detectable autocrine TGF-beta activity. The hypothesis that epigenetic mechanisms are responsible for these subsets will be tested in this cycle of the project. Other preliminary evidence indicates that loss of autocrine TGF- beta leads to the acquisition of growth factor independence for DNA synthesis. Growth factor independence is mediated in part by increased autocrine positive TGF-alpha activity. Exogenous TGF-beta and mitogen treatment have been shown to modulate cell cycle elements controlling cyclin dependent kinase activation in opposite directions. Therefore, loss of autocrine TGF-beta along with the associated changes in autocrine TGF-alpha activity may lead to impaired ability of the cell to modulate its cell cycle control elements. The hypothesis that loss of autocrine TGF-beta leads to an imbalance favoring activated cyclin dependent kinases over their inhibitors will be tested in this cycle of the project.
Specific Aims for addressing the hypothesis referred to above are: 1. Determination of the autocrine mechanisms of TGF- beta in maintaining control of cell cycle transit; 2. Characterization of control of expression of RI and RII; and 3. Characterization of epigenetic disruption of RI and RII expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038173-11
Application #
2376780
Study Section
Special Emphasis Panel (ZRG2-ET-2 (01))
Project Start
1986-07-01
Project End
1997-10-31
Budget Start
1997-03-01
Budget End
1997-10-31
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Toledo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Leiphrakpam, Premila D; Brattain, Michael G; Black, Jennifer D et al. (2018) TGF? and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells. J Biol Chem 293:8242-8254
Bailey, Katie L; Agarwal, Ekta; Chowdhury, Sanjib et al. (2017) TGF?/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PLoS One 12:e0176096
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
Leiphrakpam, Premila D; Rajput, Ashwani; Mathiesen, Michelle et al. (2014) Ezrin expression and cell survival regulation in colorectal cancer. Cell Signal 26:868-79
Agarwal, Ekta; Chaudhuri, Anathbandhu; Leiphrakpam, Premila D et al. (2014) Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer. BMC Cancer 14:145
Chowdhury, Sanjib; Ongchin, Melanie; Sharratt, Elizabeth et al. (2013) Intra-tumoral heterogeneity in metastatic potential and survival signaling between iso-clonal HCT116 and HCT116b human colon carcinoma cell lines. PLoS One 8:e60299
Agarwal, Ekta; Brattain, Michael G; Chowdhury, Sanjib (2013) Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal 25:1711-9
Chowdhury, Sanjib; Ongchin, Melanie; Wan, Guanghua et al. (2013) Restoration of PTEN activity decreases metastases in an orthotopic model of colon cancer. J Surg Res 184:755-60
Hedrick, Erik D; Agarwal, Ekta; Leiphrakpam, Premila D et al. (2013) Differential PKA activation and AKAP association determines cell fate in cancer cells. J Mol Signal 8:10

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