Glioblastoma multifore(GBM) is one of the most aggressive human cancers with medium survival time between one and three years. Its high tendency to infiltrate into adjacent brain tissue impedes complete surgical excision. In addition, the resistance to radiation and chemotherapy featured by invasive cells lies behind the recurrence of GBM. Dr. Maria Ruggieri and her colleagues at The Feinstein Institute for Medical Research have identified a new type of MAPkinase that mediates both invasion and treatment-resistance of glioblastomas. MRK can be activated by extracellular lipid lysophosphatidic acid (LPA), a mediator that elicits both mitogenic and motogenic signals in tumor cells. In one of their current studies they are exploring the role of MRK in the LPA induced tumor cell invasion.
Dr. Ruggieri is presenting her study at the American Association for Cancer Research annual meeting going on this week in Denver.
Dr. Ruggieri and Dr. Marc Symons used gene silencing technique to down regulate endogenous levels of various signaling molecules to address their relationship in the signaling pathway stimulated by LPA and mediated by MRK. They used trans-well invasion assay to study cell invasion of glioblastoma cells. Their data showed that MRK down regulation impairs LPA-stimulated invasion of glioblastoma cell lines. In the meantime, MRK depletion reduces LPA-mediated stimulation of the ERK and p38 MAP kinase signaling pathways. MRK-depleted cells also demonstrate increased levels of phosphorylated myosin light chain, which is correlated with sustained myosin activity. MRK can be activated by ionizing radiation (IR). Depletion of MRK by RNA interference leads to the failure of radiation induced cell cycle arrest, but enhances radiosensitivity of the cells. Recent in vitro studies revealed that ionizing radiation increases the invasiveness of glioblastoma. This side-effect of radiation is a potential limitation to its clinical benefit and may even contribute to tumor progression. They found that down regulation of MRK significantly reduce the glioblastoma invasion triggered by sub-lethal dose of radiation treatment. Combining all these observations they suggest that MRK is potentially a pharmaceutical target for both enhancing the response of radiation therapy and reducing its side-effect.
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