Smoothened as a Novel Signal Stabilization Scaffold in Doxorubicin Resistance

Smoothened 作为阿霉素耐药性的新型信号稳定支架

• 批准号: 10595082
• 负责人: RALF LANDGRAF
• 金额: $ 47.05万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595082
• 关键词: Adult; Anthracycline; Antineoplastic Agents; Area; B-Cell Lymphomas; Binding; Biological Markers; Cardiotoxicity; Cell Line; Cell surface; Cells; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Data; Diffuse; Dose; Doxorubicin; Drug resistance; Erinaceidae; Event; Investigation; Link; Lymphoma; Lymphoma cell; Mediating; Membrane; Modeling; Modification; Molecular; Nature; Oncogenic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Protein Processing; Protein Dephosphorylation; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Refractory; Refractory Disease; Relapse; Research; Resistance; Role; Route; Running; Sampling; Signal Pathway; Signal Transduction; TRAF6 gene; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Transducers; Treatment Protocols; Ubiquitination; biological specimen archives; cancer therapy; clinically relevant; inhibitor; innovation; insight; internal control; knock-down; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; novel; overexpression; patient derived xenograft model; pharmacologic; receptor; recruit; response; scaffold; seven-transmembrane G-protein-coupled receptor; smoothened signaling pathway; therapeutic target; translational potential; tumor; ubiquitin-protein ligase

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.

平滑作为一种新的“信号稳定支架”治疗阿霉素耐药性

项目成果

Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling.

• DOI: 10.1038/s41374-021-00702-6
• 发表时间: 2022-04
• 期刊: Laboratory investigation; a journal of technical methods and pathology
• 作者: Agarwal NK;Kim CH;Kunkalla K;Vaghefi A;Sanchez S;Manuel S;Bilbao D;Vega F;Landgraf R
• 通讯作者: Landgraf R