Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy.
Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy.
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DOI：
10.1158/0008-5472.can-08-3858
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Aguirre-Ghiso JA
中科院分区：
文献类型：
--
作者：
Schewe DM;Aguirre-Ghiso JA
蛋白酶体抑制剂（Velcade）有效地排放多发性骨髓瘤（MM）细胞，部分是通过激活内质网（ER）应力凋亡信号传导。因此，我们在癌细胞中的生长和存活率。存活的细胞分数进入延长的静止状态（G0-G1停滞）表明，硼替佐米的静止细胞衰减EIF2α磷酸化和ER应力propoptoptotic proptoptotic toproptotic基因的诱导。和PKR。 ，EIF2α的dephorylation被磷酸化的模仿EIF2α-S51D突变体表达，我们的数据表明，硼替Zomib可以在治疗疗法的MM细胞中诱导生长促进。可以通过抑制EIF2α去磷酸化来阻止机制，该策略在高磷酸化状态下保持EIF2α可能是一种新型的治疗方法，可以最大程度地提高硼替Zomib诱导的凋亡并减少残留疾病并减少这种类型的癌症。
The proteasome inhibitor bortezomib (Velcade) effectively eradicates multiple myeloma (MM) cells, partly by activating endoplasmic reticulum (ER) stress apoptotic signaling. However, MM recurrences in bortezomib-treated patients are invariable. We have shown that ER stress signaling can also induce growth arrest and survival in cancer cells. Thus, we hypothesized that bortezomib therapy could induce quiescence and survival of residual MM cells, contributing to disease recurrence. Here, we report that in MM cells, proteasome inhibition with MG-132 or bortezomib results in a surviving cell fraction that enters a prolonged quiescent state (G0–G1 arrest). Mechanism analysis revealed that bortezomib-surviving quiescent cells attenuate eIF2α phosphorylation and induction of the ER stress proapoptotic gene GADD153. This occurs independently of the eIF2α upstream kinases PERK, GCN2, and PKR. In contrast, the prosurvival ER-chaperone BiP/Grp78 was persistently induced. The bortezomib-surviving quiescent fraction could be eradicated by a simultaneous or sequential combination therapy with salubrinal, an inhibitor of GADD34-PP1C phosphatase complex, and, in consequence, eIF2α dephosphorylation. This effect was mimicked by expression of a phosphorylated mimetic eIF2α-S51D mutant. Our data indicate that bortezomib can induce growth arrest in therapy-surviving MM cells and that attenuation of eIF2α phosphorylation contributes to this survival. Most importantly, this survival mechanism can be blocked by inhibiting eIF2α dephosphorylation. Thus, strategies that maintain eIF2α in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer.