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

描述(申请人提供)：三氧化二砷(ATO)是美国食品和药物管理局(FDA)批准的一种治疗急性髓细胞白血病(APL)亚型的药物。砷和/或用于治疗其他恶性肿瘤的其他药物化合物也有临床开发的潜力。然而，到目前为止，砷作为APL以外的单一药物还没有显示出显著的临床活性，这可能是因为激活了抵消其活性的负反馈通路。我们研究组的主要目标是研究砷在髓系白血病中的作用机制，了解砷激活的负反馈通路，并寻找可以与其结合以改善患者临床结果的药物。在这项建议中，我们试图研究AMPK在砷的抗白血病作用中的作用，以及这如何有助于诱导mTOR作为负反馈循环以及在诱导自噬中的作用。我们实验室先前的研究表明，在用砷处理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的直接负性调节因子，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。我们还认为，由于AMPK可以负向调节VSP34，所以砷通过抑制AMPK而通过Vps34/Beclin/UVRAG复合体诱导自噬。在目的2中，我们将联合砷和AMPK激活剂，研究AMPK信号在体内诱导急性髓系白血病(AML)异种移植模型抗白血病效应中的作用。总之，这项工作应该确定砷激活负反馈通路的机制，并可能导致治疗白血病的新药物的开发。

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.