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

描述(申请人提供)：多发性骨髓瘤是一种骨髓浆细胞瘤，目前是一种不治之症。然而，最近取得了一些进展，包括蛋白酶体抑制剂Bortezomib(VELCADE)在难治性和复发性骨髓瘤中的成功应用。虽然最初被认为是通过抑制核因子-βB来杀死细胞，但对先前数据的重新评估以及文献中的数据表明，尽管抑制核因子-βB可能在蛋白酶体抑制剂诱导的细胞死亡中发挥作用，但它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取决于其正常对应的浆细胞的功能。浆细胞具有复杂的内质网，以确保抗体的正确折叠和组装。这是由于在浆细胞发育过程中，未折叠蛋白反应(UPR)的生理成分被激活。我们假设浆细胞和骨髓瘤细胞对额外的内质网应激高度敏感，抑制蛋白酶体通过抑制错误折叠/受损的蛋白质从内质网逆行转移到细胞质而诱导骨髓瘤细胞凋亡。这导致内质网中蛋白质的积累和UPR末端成分的激活。我们提出了三个特定的目标来确定UPR和ER应激在蛋白酶体抑制剂诱导骨髓瘤细胞凋亡中的作用。我们已经证明了蛋白酶体抑制会导致UPR末端成分的激活，因此在第一个特定的目的中，我们将确定UPR在蛋白酶体抑制剂敏感性中的作用。在第二个特定目标中，我们将重点研究内质网相关降解(ERAD)在蛋白酶体抑制剂诱导的细胞凋亡中的作用。最后，目前尚不清楚内质网应激如何导致细胞凋亡程序的激活。我们已经发表了caspase-12和caspase-4在内质网应激诱导的细胞凋亡中都不是必需的。因此，在第三个目标中，我们将采用系统的方法来确定蛋白酶体抑制剂启动内质网应激诱导细胞凋亡的机制。了解导致对蛋白酶体抑制剂诱导的细胞凋亡敏感的机制(S)将可能为这类药物用于其他高度专门化的分泌细胞癌提供理论基础，并为骨髓瘤的ER途径治疗提供更多靶点。

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.