Zachary Kohutek, PhD, 2009

Zachary Kohutek, PhD, 2009

Title: Protein kinase C regulation of matrix metalloproteinases and invasive growth in glioblastoma multiforme

Abstract:

Glioblastomas (GBMs) are highly malignant and invasive brain tumors that are associated with an extremely poor prognosis and are resistant to traditional therapies. As glioblastoma cells acquire their infiltrative phenotype, they overexpress various matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases that cleave extracellular matrix and cell surface protein substrates to induce cell proliferation, adhesion, migration and invasion. Because of their key role in GBM, understanding the functions of MMPs, as well as the mechanisms by which they are regulated, is critical to elucidating the molecular events that drive GBM invasive growth. Among the potential regulators of MMPs are the protein kinase C (PKC) family of serine/threonine kinases, which promote growth and invasion of many tumor types.

Here we demonstrate that PKC-mediated regulation of MMPs is important in the formation and maintenance of GBMs. We first show that PKC-α promotes the function of the MMP-related protease ADAM-10 by increasing its translocation to the plasma membrane. This increased activity of ADAM-10 then leads to cleavage of the cell adhesion molecule N-cadherin, causing increased GBM cell migration. We further demonstrate that PKC-α, as well as PKC-δ, is required for the transcription of MMP-9 in GBM cells. MMP-9 has previously been shown to be a major protease involved in GBM cell survival and invasion. Here we demonstrate that gene silencing of MMP-9, or its regulators PKC-α and PKC-δ, leads to decreased GBM invasive growth in a xenograft mouse model. Taken together, these studies provide some insight into the mechanisms controlling the invasive capacity of glioblastomas, which will be essential for developing novel therapeutics that can increase long-term survival.

Full dissertation:

http://search.proquest.com/docview/305013892