Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells.
Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells.
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DOI：
10.18632/oncotarget.6365
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Holstein SA
中科院分区：
文献类型：
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作者：
Dykstra KM;Allen C;Born EJ;Tong H;Holstein SA
多发性骨髓瘤（MM）以产生单克隆蛋白（MP）为特征。我们之前已经证明，类异戊二烯生物合成途径（IBP）的破坏通过破坏Rab GTPase活性导致MP分泌受阻，导致MM细胞中未折叠蛋白反应增强和随后的凋亡。自噬是由细胞应激源诱导的，包括营养剥夺和内质网应激。IBP抑制剂已被证明对自噬有不同的影响。在这里，我们定义了IBP抑制剂利用特异性药理学抑制剂对MM细胞自噬通量的不同影响的机制。我们证明IBP抑制诱导自噬的净增加，这是由于类异戊二烯生物合成的破坏，而不是直接的香叶基转移酶抑制。IBP抑制剂诱导的自噬是一种细胞防御机制，因为自噬抑制剂巴菲霉素A1可以增强GGPP耗损的细胞毒性作用，但不会抑制香叶基香叶转移酶。免疫荧光显微镜研究显示，IBP抑制剂破坏内质网对高尔基体的单克隆轻链蛋白运输，并且该蛋白不是其他降解途径（如聚合体和自噬体）的底物。这些研究支持进一步开发特异性GGTase II抑制剂作为抗骨髓瘤药物。
Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents.