Proteosome inhibitor sensitivity in multiple myeloma: The role of ER stress

多发性骨髓瘤中的蛋白酶体抑制剂敏感性：内质网应激的作用

• 批准号: 8196866
• 负责人: Lawrence H. Boise
• 金额: $ 31.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196866
• 关键词: Antibodies; Antioxidants; Apoptosis; Apoptotic; Arsenic Trioxide; Bone Marrow; Bortezomib; Cell Death; Cells; Complex; Cytoplasm; Data; Disease; Drops; Endoplasmic Reticulum; Evaluation; Gene Expression; Hydrogen Peroxide; Malignant Neoplasms; Multiple Myeloma; Neoplasms; Noxae; Pathway interactions; Physiological; Plasma Cells; Play; Production; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Published Comment; Publishing; Refractory; Relapse; Role; Secretory Cell; Stress; Velcade; Vision; Yeasts; caspase 12; cell killing; human CASP4 protein; inhibitor/antagonist; multicatalytic endopeptidase complex; novel; plasma cell development; programs; promoter; response; transcription factor

DESCRIPTION (provided by applicant): Multiple myeloma is a neoplasia of plasma cells in the bone marrow and is presently an incurable disease. However recent advances have been made including the successful use of the proteasome inhibitor, bortezomib (Velcade) in refractory and relapsed myeloma. While initially believed to kill cells through inhibition of NF-?B, re-evaluation of previous data as well as data presented within suggest that while inhibition of NF-?B may play a role in proteasome inhibitor induced cell death, it is unlikely to be the primary factor that determines myeloma cell sensitivity. We believe that the sensitivity of the myeloma cell lies with the function of its normal counterpart, the plasma cell. Plasma cells possess a complex endoplasmic reticulum to assure proper folding and assembly of antibodies. This is due to the activation of the physiologic component of the unfolded protein response (UPR) during plasma cell development. We hypothesize that plasma cells and by extension myeloma cells are highly susceptible to additional ER stress and that proteasome inhibition induces apoptosis in myeloma through inhibition of the retrograde translocation of misfolded/damaged proteins from the ER to the cytoplasm. This results in the accumulation of proteins in the ER and the activation of the terminal components of the UPR. We propose three specific aims to determine the role of the UPR and ER stress in proteasome inhibitor-induced apoptosis in myeloma cells. We have demonstrated that proteasome inhibition results in the activation of the terminal components of the UPR therefore in the first specific aim, we will determine the role of the UPR in proteasome inhibitor sensitivity. In the second specific aim we will focus on the role of endoplasmic reticulum associated degradation (ERAD) in proteasome inhibitor induced apoptosis. Finally it is not clear how ER stress results in the activation of an apoptotic program. We have published that neither caspase-12 nor caspase-4 are necessary for ER stress-induced apoptosis. Therefore in the third aim we will take a systematic approach to determine the mechanism of proteasome inhibitor initiated ER stress-induced apoptosis. Understanding the mechanism(s) that result in sensitivity to proteasome inhibitor-induced apoptosis will likely provide rationale for the use of this class of agents in other cancers of highly specialized secretory cells as well as provide additional targets for therapy within the ER pathway for myeloma.

描述（由申请人提供）：多发性骨髓瘤是骨髓中浆细胞的肿瘤，目前是一种无法治愈的疾病。然而，最近的进步已经取得了进步，包括成功使用蛋白酶体抑制剂硼替佐米（Velcade）在难治性中并复发骨髓瘤。虽然最初被认为通过抑制NF-？b杀死细胞，但对先前数据的重新评估以及内部显示的数据表明，尽管抑制NF-？B可能在蛋白酶体抑制剂诱导的细胞死亡中起作用，但不太可能是决定骨髓瘤细胞敏感性的主要因素。我们认为，骨髓瘤细胞的敏感性在于其正常对应物浆细胞的功能。血浆细胞具有复杂的内质网，以确保抗体的适当折叠和组装。这是由于浆细胞发育过程中未折叠蛋白反应（UPR）的生理成分激活。我们假设血浆细胞和延伸性骨髓瘤细胞高度易受额外的ER应激，并且蛋白酶体抑制通过抑制逆行逆转转移而受损/受损的蛋白质从ER到细胞质的逆转易流易位诱导骨髓瘤的凋亡。这导致蛋白质在ER中的积累和UPR的末端成分的激活。我们提出了三个特定的目的，以确定UPR和ER应激在蛋白酶体抑制剂诱导的骨髓瘤细胞中的作用。我们已经证明，蛋白酶体抑制作用导致UPR的末端成分的激活，因此在第一个特定目的中，我们将确定UPR在蛋白酶体抑制剂敏感性中的作用。在第二个特定目的中，我们将重点介绍内质网相关降解（ERAD）在蛋白酶体抑制剂诱导的细胞凋亡中的作用。最后，尚不清楚ER应力如何导致凋亡程序的激活。我们已经发表了CASPASE-12和CASPASE-4对于ER应激诱导的细胞凋亡是不需要的。因此，在第三个目的中，我们将采用系统的方法来确定蛋白酶体抑制剂的机制引发了ER应激诱导的凋亡。了解导致蛋白酶体抑制剂诱导的凋亡敏感的机制可能会为在其他高度专业分泌细胞的其他癌症中使用该类药物的使用提供理由，并为骨髓瘤的ER途径提供其他靶标。

项目成果

Acquisition of a multidrug-resistant phenotype with a proteasome inhibitor in multiple myeloma.

• DOI: 10.1038/leu.2009.123
• 发表时间: 2009-11
• 期刊: Leukemia
• 影响因子: 11.4