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Grant Details

Grant Number: 5R01CA090932-04 Interpret this number
Primary Investigator: Boss, Gerry
Organization: University Of California San Diego
Project Title: Analysis of Ras and Rho Activation in Prostate Cancer
Fiscal Year: 2005


Abstract

Prostate cancer is the most common cancer in men and, after lung cancer, is the second leading cause of cancer deaths in men. Because a large number of prostate cancers remain localized and never spread, a critical challenge in the management of prostate cancer is trying to determine which patients should be treated aggressively; this challenge arises in part because of the lack of biomarkers that predict the biological behavior of prostate cancer. Ras and Rho are small G proteins involved in regulating cell growth, cell adhesion and motility, and apoptosis. In some cell systems, a constitutively- activated Ras is sufficient to induce cellular transformation and in animal tumor models, Rho clearly plays a role in cell migration and the development of metastases. We have developed methods to assess the activation states of Ras and Rho in human tissue and have found that Ras is highly activated, in the absence of a genetic ras mutation, in neuronal tumors and in breast and lung cancers. The basis for increased Ras activation appeared to be through overexpression of a growth factor receptor that signals through Ras, e.g., the epidermal growth factor (EGF) or ErbB-2 receptor, or through decreased activity of a RasGTPase. A mutated constitutively-activated EGF receptor is expressed in a high percentage of prostate cancers and the wild type EGF receptor and the ErbB-2 and ErbB-3 receptors appear to be overexpressed in some prostate cancers. In addition, prostatic stromal and epithelial cells produce a large number of growth factors and biopeptides leading to paracrine and autocrine stimulation of Ras and Rho. Thus, even though activating mutations in the ras gene are rare in prostate cancer, we hypothesize that Ras, as well as Rho, may be activated in prostate cancer and preliminary data on a small series of cancers support this hypothesis. The tumors with increased Ras and Rho activation appeared to exhibit a more malignant phenotype and we additionally hypothesize that high Ras or Rho activation may be a biomarker for a more aggressive tumor. We now propose to study two large series of prostate cancers, one prospectively and one retrospectively, in order to test these two hypotheses.



Publications

The nitric oxide scavenger cobinamide profoundly improves survival in a Drosophila melanogaster model of bacterial sepsis.
Authors: Broderick K.E. , Feala J. , McCulloch A. , Paternostro G. , Sharma V.S. , Pilz R.B. , Boss G.R. .
Source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2006 Sep; 20(11), p. 1865-73.
PMID: 16940158
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Cyanide detoxification by the cobalamin precursor cobinamide.
Authors: Broderick K.E. , Potluri P. , Zhuang S. , Scheffler I.E. , Sharma V.S. , Pilz R.B. , Boss G.R. .
Source: Experimental biology and medicine (Maywood, N.J.), 2006 May; 231(5), p. 641-9.
PMID: 16636313
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Cyclic GMP-dependent protein kinase regulates CCAAT enhancer-binding protein beta functions through inhibition of glycogen synthase kinase-3.
Authors: Zhao X. , Zhuang S. , Chen Y. , Boss G.R. , Pilz R.B. .
Source: The Journal of biological chemistry, 2005-09-23; 280(38), p. 32683-92.
EPub date: 2005-07-29.
PMID: 16055922
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Nitric oxide inhibits mammalian methylmalonyl-CoA mutase.
Authors: Kambo A. , Sharma V.S. , Casteel D.E. , Woods V.L. , Pilz R.B. , Boss G.R. .
Source: The Journal of biological chemistry, 2005-03-18; 280(11), p. 10073-82.
EPub date: 2005-01-12.
PMID: 15647267
Related Citations

Nitric oxide scavenging by the cobalamin precursor cobinamide.
Authors: Broderick K.E. , Singh V. , Zhuang S. , Kambo A. , Chen J.C. , Sharma V.S. , Pilz R.B. , Boss G.R. .
Source: The Journal of biological chemistry, 2005-03-11; 280(10), p. 8678-85.
EPub date: 2005-01-04.
PMID: 15632180
Related Citations

Reactions of nitric oxide with vitamin B12 and its precursor, cobinamide.
Authors: Sharma V.S. , Pilz R.B. , Boss G.R. , Magde D. .
Source: Biochemistry, 2003-07-29; 42(29), p. 8900-8.
PMID: 12873151
Related Citations

Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer.
Authors: Khare S. , Cerda S. , Wali R.K. , von Lintig F.C. , Tretiakova M. , Joseph L. , Stoiber D. , Cohen G. , Nimmagadda K. , Hart J. , et al. .
Source: Cancer research, 2003-07-01; 63(13), p. 3517-23.
PMID: 12839936
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Synergism between calcium and cyclic GMP in cyclic AMP response element-dependent transcriptional regulation requires cooperation between CREB and C/EBP-beta.
Authors: Chen Y. , Zhuang S. , Cassenaer S. , Casteel D.E. , Gudi T. , Boss G.R. , Pilz R.B. .
Source: Molecular and cellular biology, 2003 Jun; 23(12), p. 4066-82.
PMID: 12773552
Related Citations

Oncogenic Ras leads to Rho activation by activating the mitogen-activated protein kinase pathway and decreasing Rho-GTPase-activating protein activity.
Authors: Chen J.C. , Zhuang S. , Nguyen T.H. , Boss G.R. , Pilz R.B. .
Source: The Journal of biological chemistry, 2003-01-31; 278(5), p. 2807-18.
EPub date: 2002-11-11.
PMID: 12429740
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