Using a gene array, we have identified that expression of Raf kinase inhibitor protein (RKIP) is down-regulated in prostate cancer metastases. RKIP inhibits JAK/STAT activation and Raf-mediated activation of MEK/ERK. Immunohistochemistry confirmed that RKIP is present in normal prostate and primary prostate tumors, but absent in prostate cancer metastases. Furthermore, we have demonstrated that transfection of a metastatic prostate cancer cell line with RKIP cDNA prevents metastasis in a murine model while having no effect on growth rate of the primary tumor and transfection of a non-metastatic prostate cancer cell line with antisense RKIP promotes metastasis. Taken together, these data lead us to hypothesize RKIP is a prostate cancer metastasis-suppressor gene, whose loss promotes metastasis through MEK/ERK and JAK/STAT. To test our hypothesis, we will perform the following specific aims: 1. Determine the extent of RKIP's metastasis suppressor activity in vivo. Using several novel prostate cancer cell lines we will determine the effect of modulating RKIP levels on metastasis in murine models. 2. Identify the cellular mechanism(s) through which RKIP dysregulation promotes metastasis. We will evaluate the effect of manipulating RKIP levels on pro-metastatic parameters including angiogenesis, endothelial adhesion and invasiveness. Once we identify a target molecule based on these in vitro studies we will use inhibitors in vivo to determine if blocking these activities inhibits loss of RKIP-mediated metastasis. 3.Determine the signaling pathways through which decreased RKIP expression mediates metastasis. We will evaluate the effects of modulating the activities of the JAK/STAT and MEK signaling pathways on in vitro parameters including invasion, proliferation and apoptosis. Subsequently, we will determine the effect on establishment of metastases in vivo. Furthermore, we will determine if any pro-metastatic cellular phenotypes identified in Aim 2 are modulated by these signaling pathways. when completed, we hope this work will lead to a better understanding of the mechanisms through which RKIP suppresses metastasis and hopefully identify specific targets to inhibit metastasis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098513-04
Application #
7195704
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mohla, Suresh
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$237,918
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Urology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Honglai; Wu, Jianguo; Keller, Jill M et al. (2012) Transcriptional regulation of RKIP expression by androgen in prostate cells. Cell Physiol Biochem 30:1340-50
Keller, Evan T (2011) Role of Raf Kinase Inhibitor Protein in Pathophysiology of Prostate Cancer. For Immunopathol Dis Therap 2:89-94
DeHaan, Alyse M; Wolters, Natalie M; Keller, Evan T et al. (2009) EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling. Prostate 69:528-37
Woods Ignatoski, Kathleen M; Grewal, Navdeep K; Markwart, Sonja M et al. (2008) Loss of Raf kinase inhibitory protein induces radioresistance in prostate cancer. Int J Radiat Oncol Biol Phys 72:153-60
Beach, S; Tang, H; Park, S et al. (2008) Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene 27:2243-8
Diehl, Kathleen M; Keller, Evan T; Ignatoski, Kathleen M Woods (2007) Why should we still care about oncogenes? Mol Cancer Ther 6:418-27
Fu, Zheng; Kitagawa, Yasuhide; Shen, Ronglai et al. (2006) Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Prostate 66:248-56
Keller, Evan T; Fu, Zheng; Brennan, Meghan (2005) The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein. J Cell Biochem 94:273-8
Chen, Chen; Koh, Amy J; Datta, Nabanita S et al. (2004) Impact of the mitogen-activated protein kinase pathway on parathyroid hormone-related protein actions in osteoblasts. J Biol Chem 279:29121-9
Keller, Evan T; Fu, Zheng; Brennan, Meghan (2004) The role of Raf kinase inhibitor protein (RKIP) in health and disease. Biochem Pharmacol 68:1049-53

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