This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SUBPROJECT DESCRIPTION (07/01/2007 - 04/30/2008) Apoptosis is the major mechanism of non-necrotic cell death that occurs in the drug treatment of malignant tumors. The current view, regarding the chemotherapeutic induction of apoptosis, does not acknowledge the possibility that the process of apoptosis could exacerbate the invasive characteristics of the tumor. Our previous data show that upon the induction of apoptosis in the LN18 glioblastoma there is a down regulation of a number of cell surface receptors including: insulin receptor (INSR), insulin growth factor receptors 1 and 2 (IGF1R and IGF2R), epidermal growth factor receptor (EGFR), and a variety of alpha and beta components of integrins. Apoptosis was induced by either MK886, a known inhibitor of five-lipoxygenase-activating protein (FLAP), or staurosporine, a known inhibitor of a number of protein kinases including protein kinase C (PKC). These previous data also indicate that broad metalloproteinase inhibitors effectively reverse the apoptotic down regulation of the surface receptors even when added 6-7 hr after the induction of apoptosis. A predominant characteristic of cancer cells is their ability to invade surrounding tissue. Glioblastoma is a type of brain cancer that is very invasive and highly malignant. Chemotherapeutic regimens for glioblastomas and other high grade gliomas have fallen short of providing effective treatment. Although recent drug treatments for glioblastomas have increased tumor shrinkage with an increase in median survival times, there is no evidence for increased survival rates. The focus of this subcontract is to determine if cell death mechanisms enhance the production and secretion of metalloproteinases in glioblastoma cells which in turn enhance the invasiveness of the tumor cells.
NIH ExPorter
NIH ExPorter