The overall goal of this project is to investigate the molecular basis for and biological effects of ATG4B activation in glioblastoma (GBM), the most common and aggressive primary brain tumor. Our preliminary results, as well as the results of others, demonstrate an important role for ATG4B in autophagy, a conserved catabolic process for regulating cellular energetic balance as well as cellular response to stress. Cancer cells use autophagy: (1) to remove damaged organelles and damaged and non-functioning proteins, and to recycle highly demanded nutrients to further tumor growth; and (2) as a survival mechanism in response to therapy. A key activity of ATG4B is its conversion of LC3 to LC3-I/II for autophagysome integration, which, in turn, is necessary for tumor cell survival, continued growth, and for tumor cell autophagic response to therapies. We show here that ATG4B activity is regulated by MST4, a serine/threonine kinase that induces robust phosphorylation ATG4B at serine 383. This provides the basis for the overarching hypothesis of this proposal: that MST4-induced phosphorylation of ATG4B is required for GBM autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We will address this hypothesis in the context of three specific aims: 1) determine how MST4 induces phosphorylation of ATG4B, and in doing so influences GBM autophagy and tumorigenicity; 2) determine the role of phosphorylation of ATG4B in autophagy, GBM tumorigenicity, and association with GBM patient prognosis.; and 3) determine whether suppressing ATG4B and/or MST4 affects GBM response to radiation and temozolomide (TMZ) treatments. The proposed studies are significant in that this project will establish ATG4B as an essential contributor to GBM growth and response to therapy, and that these activities depend on MST4-induced phosphorylation. This knowledge, in turn, will help identify points of therapeutic intervention for improved treatment outcomes for GBM patients.
In malignant glioblastoma (GBM), autophagy-mediated intracellular recycling sustains tumor metabolism, growth and survival favors tumor growth and progression. Autophagy in response to therapeutic treatments such as radiation and chemotherapies also provides a mechanism for GBM cell to survive and acquire resistance to therapies. This application will test a hypothesis that ATG4B, a key enzyme in autophagic process contributes to GBM autophagic response, malignant phenotypes, and response to therapy, by MST4 activation of ATG4B through S383 phosphorylation.
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