Autophagy Regulation of Glioblastoma Tumorigenesis and Responses to Therapy

 描述(申请人提供)：这个项目的总体目标是研究ATG4B激活在胶质母细胞瘤(GBM)中的分子基础和生物学效应，胶质母细胞瘤是最常见和最具侵袭性的原发脑瘤。我们的初步结果以及其他人的结果表明，ATG4B在自噬中发挥了重要作用，自噬是一种调节细胞能量平衡和细胞应激反应的保守分解代谢过程。癌细胞利用自噬：(1)去除受损的细胞器和受损的和不起作用的蛋白质，并回收高需求的营养物质，以进一步促进肿瘤的生长；(2)作为治疗反应的生存机制。ATG4B的一个关键活性是将Lc3转化为Lc3-I/II以进行自噬整合，这反过来又是肿瘤细胞存活、持续生长和肿瘤细胞对治疗的自噬反应所必需的。我们在这里表明ATG4B的活性是由MST4调节的，MST4是一种丝氨酸/苏氨酸激酶，它诱导丝氨酸383处的ATG4B强烈的磷酸化。这为这一建议的总体假设提供了基础：MST4诱导的ATG4B的磷酸化是GBM自噬反应所必需的，这反过来又有助于肿瘤细胞的生存、生长和对治疗的抵抗。我们将在三个特定目标的背景下解决这一假设：1)确定MST4如何诱导ATG4B的磷酸化，并在此过程中影响GBM的自噬和致瘤性；2)确定ATG4B的磷酸化在自噬、GBM致瘤性中的作用，以及与GBM患者预后的关系；以及3)确定抑制ATG4B和/或MST4是否影响GBM对放射和替莫唑胺(TMZ)治疗的反应。拟议的研究具有重要意义，因为该项目将使ATG4B成为GBM生长和治疗反应的重要贡献者，并且这些活动依赖于MST4诱导的磷酸化。这一知识反过来将有助于确定治疗干预点 改善了GBM患者的治疗结果。

 DESCRIPTION (provided by applicant): 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.