Abstract

The overall hypothesis addressed in this project is that the gastrointestinal (Gl) peptide parathyroid hormone-related protein (PTHrP) plays an important regulatory role in the gut, and its dysregulation contributes to disease via aberrant regulation of the phosphatidylinositol-3-kinase (PI3K) pathway. We show that PTHrP increases colon cancer cell xenograft growth in vivo. PTHrP expression is higher in metastatic vs. non-metastatic colon cancer cells, and there is a direct correlation of PTHrP levels with pro-invasive integrin expression and the migratory and invasive potential of these cells in vitro. We find that the PI3K pathway mediates these effects. The focus of this project is to understand the molecular mechanisms via which PTHrP promotes colon cancer cell invasion, by pursuing three Aims. (1) The mechanism(s) governing the upregulation of PI3K by PTHrP will be determined, by asking whether this occurs via an interaction between the PI3K p85 This aim will be accomplished using such techniques as transfection with dominant-negative mutants, determination of the protein levels by Western immunoblotting and immunocytochemistry, and direct activity measurements. (3) The pathway(s) via which PTHrP upregulates pro-invasive integrin expression will be addressed using Northern blot analysis to detect changes in integrin mRNA levels, pulse-chase analysis to detect alterations in the rate of integrin synthesis and turnover, and FACS analysis to detect changes in integrin intracellular mobilization in PTHrP-overexpressing vs. control colon cancer cells. These studies will allow us to identify the mechanism(s) by which PTHrP promotes invasion and metastases of colon cancer cells, and should ultimately allow the development of new therapeutic strategies aimed at controlling this process.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK035608-23
Application #
7790562
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
23
Fiscal Year
2009
Total Cost
$166,037
Indirect Cost

  Institution

Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555

  Publications

Bhatia, Vandanajay; Cao, Yanna; Ko, Tien C et al. (2016) Parathyroid Hormone-Related Protein Interacts With the Transforming Growth Factor-?/Bone Morphogenetic Protein-2/Gremlin Signaling Pathway to Regulate Proinflammatory and Profibrotic Mediators in Pancreatic Acinar and Stellate Cells. Pancreas 45:659-70
Staloch, Dustin; Gao, Xuxia; Liu, Ka et al. (2015) Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. J Mol Med (Berl) 93:1085-1093
Mrazek, Amy A; Porro, Laura J; Bhatia, Vandanajay et al. (2015) Apigenin inhibits pancreatic stellate cell activity in pancreatitis. J Surg Res 196:8-16
Gao, Xuxia; Cao, Yanna; Staloch, Dustin A et al. (2014) Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One 9:e89114
Bhatia, Vandanajay; Rastellini, Cristiana; Han, Song et al. (2014) Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis. Am J Physiol Gastrointest Liver Physiol 307:G533-49
Gao, Xuxia; Cao, Yanna; Yang, Wenli et al. (2013) BMP2 inhibits TGF-?-induced pancreatic stellate cell activation and extracellular matrix formation. Am J Physiol Gastrointest Liver Physiol 304:G804-13
Deng, Xiyun; Cao, Yanna; Liu, Yan et al. (2013) Overexpression of Evi-1 oncoprotein represses TGF-? signaling in colorectal cancer. Mol Carcinog 52:255-264
Cao, Yanna; Zhang, Weili; Gao, Xuxia et al. (2013) PTHrP is a novel mediator for TGF-?-induced apoptosis. Regul Pept 184:40-6
Cao, Yanna; Yang, Wenli; Tyler, Matthew A et al. (2013) Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy. Pancreas 42:301-7
Okamura, Daiki; Starr, Marlene E; Lee, Eun Y et al. (2012) Age-dependent vulnerability to experimental acute pancreatitis is associated with increased systemic inflammation and thrombosis. Aging Cell 11:760-9

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