The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma
The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma
复制标题
核因子（红细胞衍生2）样2和蛋白酶体成熟蛋白轴介导多发性骨髓瘤中的硼替佐米耐药性
DOI：
10.1074/jbc.m115.664953
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发表时间：
2015-12-11
影响因子：
4.8
通讯作者：
Orlowski, Robert Z.
中科院分区：
文献类型：
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作者：
Li, Bingzong;Fu, Jinxiang;Orlowski, Robert Z.
对蛋白酶体抑制剂Bortezomib的耐药性是一个新出现的临床问题，其机制尚未完全阐明。我们认为这可能与蛋白酶体活性增强有关，部分是通过蛋白酶体成熟蛋白(POMP)的作用。采用对波特佐米耐药的骨髓瘤模型，研究波特佐米的表达与波特佐米敏感性之间的相关性。然后使用遗传和药理学方法调节pomp的表达，以确定在细胞系和活体模型中对蛋白酶体抑制物敏感性的影响。耐药细胞系过度表达Pomp，在细胞系中抑制Pomp增强了对Bortezomib的敏感性，而在药物初治细胞中Pomp过表达则导致耐药。Pomp的过度表达与核因子(红系衍生的2)样(NRF2)水平的增加有关，并且NRF2被发现与Pomp启动子结合并激活。在对硼替佐米耐药的细胞中，NRF2的敲除降低了Pomp水平和蛋白酶体活性，而它在药物初治细胞中的过表达则增加了Pomp2和蛋白酶体的活性。NRF2抑制剂全反式维甲酸降低了耐药细胞中NRF2的水平，增加了耐药细胞中Bortezomib的抗增殖和促凋亡活性，同时降低了蛋白酶体的能力。最后，全反式维甲酸与硼替佐米的结合显示出对原始患者样本和耐药的小鼠骨髓瘤的增强活性。综上所述，这些研究证实了NRF2/pomp轴在Bortezomib耐药中的作用，并确认NRF2和pomp是这种蛋白酶体抑制剂潜在的有吸引力的化疗增敏靶点。
Resistance to the proteasome inhibitor bortezomib is an emerging clinical problem whose mechanisms have not been fully elucidated. We considered the possibility that this could be associated with enhanced proteasome activity in part through the action of the proteasome maturation protein (POMP). Bortezomib-resistant myeloma models were used to examine the correlation between POMP expression and bortezomib sensitivity. POMP expression was then modulated using genetic and pharmacologic approaches to determine the effects on proteasome inhibitor sensitivity in cell lines and in vivo models. Resistant cell lines were found to overexpress POMP, and while its suppression in cell lines enhanced bortezomib sensitivity, POMP overexpression in drug-naive cells conferred resistance. Overexpression of POMP was associated with increased levels of nuclear factor (erythroid-derived 2)-like (NRF2), and NRF2 was found to bind to and activate the POMP promoter. Knockdown of NRF2 in bortezomib-resistant cells reduced POMP levels and proteasome activity, whereas its overexpression in drug-naive cells increased POMP and proteasome activity. The NRF2 inhibitor all-trans-retinoic acid reduced cellular NRF2 levels and increased the anti-proliferative and pro-apoptotic activities of bortezomib in resistant cells, while decreasing proteasome capacity. Finally, the combination of all-trans-retinoic acid with bortezomib showed enhanced activity against primary patient samples and in a murine model of bortezomib-resistant myeloma. Taken together, these studies validate a role for the NRF2/POMP axis in bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this proteasome inhibitor.