Caveolin-1 (cav-1) is an important structural/regulatory molecule involved in many aspects of molecular transport and cell signaling. Cav-1 activities are dependent on protein levels and cell context, yet a mechanistic understanding of the biological consequences of inappropriate cav-1 expression in malignant cells has been elusive. We have shown previously that cav-1 up-regulation is associated with metastatic, androgen-insensitive prostate cancer. In studies funded by this grant we identified an underlying mechanism for the selection of cav-1 overexpression in prostate cancer cells during progression. We found that cav-1 binds to and inhibits the activities of PP1/PP2A serine /threonine phosphatases, preventing inactivation of Akt through dephosphorylation and thus sustaining levels of phospho-Akt and its oncogenic activities. Recently we demonstrated that cav-1 overexpression leads to increased levels of c-myc protein and up-regulation and secretion of VEGF, FGF2 and TGF-D1. Importantly, we have also discovered that cav-1 itself is specifically secreted by prostate cancer cells and taken up by prostate cancer cells and endothelial cells (EC). Overall our data suggest that cells expressing cav-1 can function as """"""""feeder cells"""""""" for local and potentially distant prostate cancer cells and tumor-associated EC through secretion of cav-1 and cav-1 stimulated growth factors (GF)/angiogenic cytokines (AC). In support of this concept we have shown that experimentally induced metastasis is potentiated in host transgenic mice that overexpress cav-1 and is suppressed in host cav-1-/- mice. Informed by this new information we hypothesize that through specific prosurvival/proangiogenic molecular pathways, intracellular and secreted cay-1 promote prostate cancer progression. We will test this hypothesis through specific aims to: 1) identify and characterize novel cav-1 stimulated pro-survival/angiogenic pathways in prostate cancer; 2) characterize cav-1 uptake in prostate cancer cells and EC and the modulatory effects of cav-1 on GF/AC activities in prostate cancer cells and EC; 3) identify and characterize the mechanisms that underlie the systemic effects of cav-1 on prostate cancer metastasis; and 4) analyze the role of cav-1 in benign and malignant prostate epithelial cell growth and its associated angiogenesis in novel transgenic mouse prostate reconstitution models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA068814-13
Application #
7546420
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Snyderwine, Elizabeth G
Project Start
1995-08-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
13
Fiscal Year
2008
Total Cost
$296,750
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Tahir, Salahaldin A; Kurosaka, Shinji; Tanimoto, Ryuta et al. (2013) Serum caveolin-1, a biomarker of drug response and therapeutic target in prostate cancer models. Cancer Biol Ther 14:117-26
Tahir, Salahaldin A; Yang, Guang; Goltsov, Alexei et al. (2013) Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer Res 73:1900-11
Kuo, Shu-Ru; Tahir, Salahaldin A; Park, Sanghee et al. (2012) Anti-caveolin-1 antibodies as anti-prostate cancer therapeutics. Hybridoma (Larchmt) 31:77-86
Yang, Guang; Goltsov, Alexei A; Ren, Chengzhen et al. (2012) Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer. Mol Cancer Res 10:218-29
Yang, Guang; Park, Sanghee; Cao, Guangwen et al. (2010) MMTV promoter-regulated caveolin-1 overexpression yields defective parenchymal epithelia in multiple exocrine organs of transgenic mice. Exp Mol Pathol 89:9-19
Thompson, T C; Tahir, S A; Li, L et al. (2010) The role of caveolin-1 in prostate cancer: clinical implications. Prostate Cancer Prostatic Dis 13:6-11
Tahir, Salahaldin A; Park, Sanghee; Thompson, Timothy C (2009) Caveolin-1 regulates VEGF-stimulated angiogenic activities in prostate cancer and endothelial cells. Cancer Biol Ther 8:2286-96
Watanabe, Masami; Yang, Guang; Cao, Guangwen et al. (2009) Functional analysis of secreted caveolin-1 in mouse models of prostate cancer progression. Mol Cancer Res 7:1446-55
Floryk, Daniel; Thompson, Timothy C (2008) Antiproliferative effects of AVN944, a novel inosine 5-monophosphate dehydrogenase inhibitor, in prostate cancer cells. Int J Cancer 123:2294-302
Floryk, Daniel; Thompson, Timothy C (2008) Perifosine induces differentiation and cell death in prostate cancer cells. Cancer Lett 266:216-26

Showing the most recent 10 out of 40 publications