Src requirement for u-PAR expression by HGF and hypoxia

Summary

Principal Investigator: Douglas Boyd
Abstract: The high mortality rate of prostate cancer patients reflects the spread of their disease to distant sites. The plasminogen activator, urokinase, contributes to this process by converting plasminogen to plasmin, the latter which degrades extracellular matrix. Urokinase binds to a cell surface receptor (u-PAR) specifically and receptor-bound enzyme converts plasminogen into plasmin at a faster rate than fluid-phase reactants. Since the u-PAR is required for the invasiveness of prostate cancer, how is the up-regulation of this binding site achieved? Previous reports have shown that HGF/SF increases u-PAR mRNA/protein. However, whether increased u-PAR protein is due to increased transcription or increased mRNA stability is unknown. In Specific Aim # 1, we will determine if increased u-PAR protein in prostate cancer brought about by HGF/SF is due to increased transcription or decreased mRNA turnover. We previously reported the role of an AP-2alpha related factor bound to a footprinted region (region II spanning -148/124) of the u-PAR promoter in the PMA-dependent regulation of u-PAR expression. Thus, if the HGF/SF-dependent increase in u-PAR protein is due to elevated transcription, we will also determine the role of region II-bound AP-2alpha-related factor in this up-regulation. The role of the protein tyrosine kinase c-Src in the regulation of u-PAR expression by HGF/SF is not known. Considering that other HGF/SF-dependent genes show differing c-Src requirements, using dominant negative and antisense technology and a c-Src inhibitor (PD 173955), the role of c-Src in the HGF/SF-induced expression of u-PAR will be determined in Specific Aim # 2. Previous studies have shown that hypoxia, which promotes tumor progression, up-regulates u-PAR mRNA/protein. Further, c-Src activity is increased by hypoxia in prostate cancer. Since the role of c-Src in mediating increased u-PAR expression by hypoxia has not been reported and considering that other hypoxic-inducible genes demonstrate differing c-Src-sensitivities, in Specific Aim # 3, using dominant negative and antisense expression constructs and a c-Src inhibitor we will determine if the hypoxic induction of u-PAR expression is c-Src-dependent. Whether elevated u-PAR synthesis in prostate cancer is entirely due to c-Met activation is unclear. To answer this question, we will in Specific Aim # 4, determine the ability of a ribozyme directed at c-Met synthesis to downregulate u-PAR synthesis using the in vitro and in vivo invasiveness of prostate cancer as a biological endpoint. Since we recognize the real possibility that elevated u-PAR production may also be due to factors other than c-Met, we will also determine the ability of combining the anti-c-Met ribozyme with a pharmacological antagonist (A6) to attenuate the invasiveness of prostate cancer.
Funding Period: 2003-05-01 - 2007-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin
    Chunhong Yan
    Department of Cancer Biology, University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cancer Ther 4:233-41. 2005
  2. ncbi Plasticity in urokinase-type plasminogen activator receptor (uPAR) display in colon cancer yields metastable subpopulations oscillating in cell surface uPAR density--implications in tumor progression
    Lin Yang
    Department of Cancer Biology, M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Res 66:7957-67. 2006

Detail Information

Publications2

  1. ncbi Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin
    Chunhong Yan
    Department of Cancer Biology, University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cancer Ther 4:233-41. 2005
    ..Thus, we have identified several putative, novel molecular targets of curcumin and showed that one, (ATF3) contributes to the proapoptotic effects of this compound...
  2. ncbi Plasticity in urokinase-type plasminogen activator receptor (uPAR) display in colon cancer yields metastable subpopulations oscillating in cell surface uPAR density--implications in tumor progression
    Lin Yang
    Department of Cancer Biology, M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Res 66:7957-67. 2006
    ..To our knowledge, this is the first demonstration that uPAR cell surface density is oscillatory and we propose that such an event might well contribute to tumor progression...