The role of AMPK signaling in the anti-leukemic effects of Arsenic Trioxide

描述（由申请人提供）：三氧化二砷（ATO）是美国食品和药物管理局（FDA）批准的治疗急性髓性白血病亚型急性早幼粒细胞白血病（APL）的药物。在临床开发砷和/或其他治疗其他恶性肿瘤的药物化合物方面也有潜力。然而，迄今为止，砷作为APL外的单一药物尚未显示出显著的临床活性，这可能是由于负反馈通路的激活抵消了其活性。我们课课组的主要目标是研究砷在髓性白血病中的作用机制，了解砷激活的负反馈通路，并确定可与砷联合使用的药物，以提高患者的临床疗效。在本提案中，我们试图研究AMPK在砷的抗白血病作用中的作用，以及它如何促进mTOR作为负反馈回路的诱导以及自噬的诱导。我们实验室之前的研究表明，在用砷治疗白血病细胞的过程中，mTOR通路通过一种未知的机制被激活。我们有初步的数据表明，砷直接与AMPK结合并抑制其活性。由于AMPK是mTOR的直接负调节因子，我们认为这是砷激活mTOR通路的重要机制。在目标1中，我们将研究砷如何影响AMPK的结构和功能。我们还提出，砷通过AMPK抑制VPS34/Beclin/UVRAG复合物诱导自噬，因为AMPK可以负向调节VSP34。在Aim 2中，我们将结合砷和AMPK激活剂，在急性髓性白血病（AML）的异种移植小鼠模型中研究AMPK信号在诱导砷抗白血病作用中的作用。总之，这项工作应该确定砷激活负反馈途径的机制，并可能导致白血病治疗新药的开发。

DESCRIPTION (provided by applicant): Arsenic trioxide (ATO) is a Food and Drug Administration (FDA) approved therapy for a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL). There is also potential for clinical development of arsenic and/or other medicinal compounds for the treatment of other malignancies. However, to date arsenic has not shown significant clinical activity as a single agent outside of APL, likely due to the activation of negative feedback pathways that counteract its activity. The major goal of our research group is to investigate the mechanisms of action of arsenic in myeloid leukemias, understand the negative feedback pathways activate by arsenic and identify agents that can be combined with it to enhance clinical outcomes in patients. In this proposal we seek to investigate the role of AMPK in the anti-leukemic effects of arsenic and how that contributes to the induction of mTOR as a negative feedback loop as well as in the induction of autophagy. It was previously shown in our laboratory that during treatment of leukemia cells with arsenic there is activation of the mTOR pathway through an unknown mechanism. We have preliminary data to suggest that arsenic directly binds to AMPK and inhibits its activity. Because AMPK is a direct negative regulator of mTOR, we propose that this is an important mechanism for activation of the mTOR pathway by arsenic. In Aim 1 we will investigate how arsenic affects AMPK structure and function. We also propose that arsenic through AMPK inhibition leads to induction of autophagy through the VPS34/Beclin/UVRAG complex since AMPK can negative regulate VSP34. In Aim 2 we will combine arsenic with AMPK activators to investigate the role of AMPK signaling in the induction of anti-leukemic effects of arsenic in vivo in a xenograft mouse model of acute myeloid leukemia (AML). Altogether, this work should define the mechanisms by which arsenic activates negative feedback pathways and may lead to the development of novel agents for the treatment of leukemias.