Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition
Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition
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DOI：
10.1158/0008-5472.can-06-2258
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发表时间：
2007-02-15
期刊：
影响因子：
11.2
通讯作者：
Voll, Reinhard E.
中科院分区：
文献类型：
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作者：
Meister, Silke;Schubert, Ulrich;Voll, Reinhard E.
多发性骨髓瘤是一种无法治愈的浆细胞瘤，其特征是产生大量单克隆免疫球蛋白。蛋白酶体抑制剂硼替佐米（PS-341，万珂）诱导各种恶性细胞凋亡，已被批准用于治疗难治性多发性骨髓瘤。抑制抗凋亡转录因子核因子-κ B（NF-κ B）显然有助于硼替佐米的抗肿瘤作用;然而，这种机制不能完全解释骨髓瘤细胞的异常敏感性。骨髓瘤细胞中的大量蛋白质合成固有地伴随着未折叠的蛋白质，包括缺陷性核糖体产物（DRiP），其需要被泛素-蛋白酶体系统降解。因此，我们假设硼替佐米在多发性骨髓瘤中的促凋亡作用主要是由于高蛋白生物合成的细胞中未折叠蛋白的积累。使用分泌IgG的人骨髓瘤细胞系JK-6L和鼠μ H链转染的Ag8.H骨髓瘤细胞，蛋白酶体抑制后的凋亡诱导与免疫球蛋白产生量明显相关。在免疫球蛋白高的骨髓瘤细胞中，硼替佐米触发了半胱天冬酶的激活和促凋亡CHOP的诱导，这是内质网（ER）应激诱导的末端未折叠蛋白反应的一个组成部分。在免疫球蛋白高的细胞中，硼替佐米增加促凋亡Bax的水平，同时减少抗凋亡Bcl-2。最后，在蛋白酶体转运蛋白处理的细胞中检测到IgG-DRiPs。因此，蛋白酶体抑制剂优先在具有高免疫球蛋白合成速率的细胞中诱导凋亡，所述免疫球蛋白合成速率与诱导ER应激的未折叠蛋白/DRiP的积累相关。这些发现进一步阐明了蛋白酶体抑制剂的抗肿瘤活性，并对优化临床应用具有重要意义。
Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins. The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-kappa B (NF-kappa B) apparently contributes to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs), which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting human myeloma cell line JK-6L and murine mu H-chain-transfected Ag8.H mycloma cells, apoptosis induction upon proteasome inhibition was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor-treated cells. Hence, proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing clinical applications.