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

描述（由申请人提供）：多发性骨髓瘤是骨髓中浆细胞的肿瘤，目前是一种不治之症。然而，最近的进展包括蛋白酶体抑制剂硼替佐米（万珂）在难治性和复发性骨髓瘤中的成功应用。虽然最初认为通过抑制NF-？B，重新评估以前的数据以及内提出的数据表明，虽然抑制NF-？B可能在蛋白酶体抑制剂诱导的细胞死亡中起作用，它不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物浆细胞的功能。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期间未折叠蛋白反应（UPR）的生理组分的激活。我们假设浆细胞和骨髓瘤细胞对额外的ER应激高度敏感，蛋白酶体抑制通过抑制错误折叠/受损蛋白从ER到细胞质的逆行易位诱导骨髓瘤细胞凋亡。这导致ER中蛋白质的积累和UPR末端组分的活化。我们提出了三个具体的目标，以确定蛋白酶体介导的骨髓瘤细胞凋亡中的UPR和ER应激的作用。我们已经证明，蛋白酶体抑制导致UPR末端组分的活化，因此在第一个具体目标中，我们将确定UPR在蛋白酶体抑制剂敏感性中的作用。在第二个具体的目标，我们将集中在内质网相关降解（ERAD）在蛋白酶体抑制剂诱导的细胞凋亡的作用。最后，还不清楚ER应激如何导致凋亡程序的激活。我们已经发表了caspase-12和caspase-4都不是ER应激诱导的细胞凋亡所必需的。因此，在第三个目标中，我们将采取系统的方法来确定蛋白酶体抑制剂启动内质网应激诱导凋亡的机制。了解导致对蛋白酶体抑制剂诱导的细胞凋亡敏感的机制可能会为在其他高度特化分泌细胞癌症中使用此类药物提供理论基础，并为骨髓瘤ER途径中的治疗提供额外的靶点。

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.