Smoothened as a Novel Signal Stabilization Scaffold in Doxorubicin Resistance

平滑成为阿霉素耐药的新型“信号稳定支架” 阿霉素(DXR)是癌症治疗中应用最广泛的治疗药物之一。但是，与 它的心脏毒性，由于耐药性而需要更高的剂量是治疗中的一大挑战。漫反射B- 细胞淋巴瘤(cell Lymphoma，DLBCL)是成人最常见的淋巴瘤，对DXR耐药占主导地位 限制因素，成功使用当前的基于蒽环类药物的标准疗法(CHOP)。增强型AKT 众所周知，信令与DXR敏感性的丧失有关，传统上，直接作用的机制 对其进行磷酸化/去磷酸化一直是研究的重点。最近，竞争 AKT泛素化模式已经成为平衡降解(UB-K48连锁)和 膜募集、丝氨酸/苏氨酸磷酸化和激活(UB-K63连锁)。膜局域化帕克特是 代表了最强的致癌信号。我们发现TRAF6，一种(K63)E3-连接酶，负责 在DLBCL中调节PACK的稳定性和功能。此外，我们首次观察到，这一机制 依赖于七个跨膜受体“平滑”(SMO)。SMO在RAFT中本地化 微域，招募TRAF6，启动TRAF6自动稳定和激活，从而增强 DXR抗性所需的信号。SMO的这一新角色超越了它在 Hedgehog信号转导及在DXR耐药患者样本中SMO表达升高中的反映 DLBCL。异位SMO表达或SMO基因敲除分别降低或增加DXR敏感性 淋巴瘤细胞系。在这项提案中，我们将剖析SMO的区域，这些区域是这一新功能所需要的 并识别为该浮筏局部信号稳定功能组装的交互伙伴。在……里面 此外，我们将使用患者来源的异种移植小鼠模型来评估SMO对 化疗耐药和评估现有SMO抑制剂在当前化疗中的有效性 逆转耐药性的养生法。

Smoothened as a Novel “Signal Stabilization Scaffold” in Doxorubicin Resistance Doxorubicin (DXR) is among the most widely used therapeutics in cancer treatment. However, combined with its cardiotoxicity, the need for higher dosing due to drug resistance is a major challenge in treatment. Diffuse B- Cell Lymphoma (DLBCL) is the most common lymphoma in adults, and DXR resistance is the predominant limiting factor for the successful use of current anthracycline based standard therapy (CHOP). Enhanced AKT signaling is known to be associated with loss of DXR sensitivity, and traditionally, mechanisms that directly act on its phosphorylation/dephosphorylation have been the main focus of research. More recently, competing AKT ubiquitination modes have emerged as a critical factor that balances degradation (UB-K48 linkage) versus membrane recruitment, Ser/Thr phosphorylation and activation (UB-K63 linkage). Membrane localized pAKT is represents the most potent oncogenic signal. We found that TRAF6, a (K63)E3-ligase, is responsible for regulating pAKT stability and function in DLBCL. Moreover, we observed for the first time that this mechanism is dependent on the seven transmembrane spanning receptor “Smoothened” (SMO). SMO is localized in raft microdomains, recruits TRAF6, initiates TRAF6 auto stabilization and activation, and thereby enhances signaling that is needed for DXR resistance. This novel role of SMO goes beyond its canonical role in Hedgehog signaling and is reflected in elevated SMO expression in samples from patients with DXR resistant DLBCL. Ectopic SMO expression or SMO knockdown decrease or increase DXR sensitivity respectively in lymphoma cell lines. In this proposal, we will dissect the regions of SMO that are needed for this novel function and identify the interaction partners that are assembled for this raft-localized signal stabilization function. In addition, we will use a patient derived xenograft mouse model to evaluate the contribution of SMO to chemoresistance and evaluate the utility of adding existing SMO inhibitors to the current chemotherapy regimens to reverse resistance.