Targeting GRP78 palmitoylation in glioblastomas
Glioblastoma multiforme (GBM) the most common form of brain cancer in adults with very low survival of only 15 months with less than 5% of patients surviving more than 5 years. Surgery, chemotherapy, and radiation are the treatments currently used but recurrence is very common, often with tumors that are resistant to treatment. Thus, new treatment approaches are needed. GBM is reliant on increased response to stress in the cancer cells so targeting these responses is a potential new way to treat GBM. One of the key proteins involved in increasing the response to stress in GBM cancer cells is called GRP78. In GBM cancer cells the amount of GRP78 made is dramatically increased and where it goes in the cell is changed, it goes to the surface of the cell rather than staying in an inside compartment, as it does in non-cancer cells. These changes in GRP78 are associated with more severe GBM cancers, recurrence after chemotherapy, and drug resistance. However, how the location of GRP78 changes is unknown. My lab recently showed that GRP78 is modified with a sticky tag in a process called palmitoylation when the stress response in cancer cells in increased. The sticky tag acts like a postal code that may direct GRP78 to the cell surface. To test this hypothesis, we will use GBM cells to identify where on GRP78 the sticky tag is added, and which enzymes add and remove it. We will use that information to determine if the sticky tag does indeed direct it to the cell surface and if blocking the sticky tag from being added prevents cancer spread. This project may identify new treatment options for brain cancers.
Shaun Sanders , University of Guelph
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