Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits.
Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits.
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DOI：
10.7554/elife.08153
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发表时间：
2015-09-01
期刊：
影响因子：
7.7
通讯作者：
Kampmann M
中科院分区：
文献类型：
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作者：
Acosta-Alvear D;Cho MY;Wild T;Buchholz TJ;Lerner AG;Simakova O;Hahn J;Korde N;Landgren O;Maric I;Choudhary C;Walter P;Weissman JS;Kampmann M
癌症的特征，包括快速生长和非整倍体，可导致非癌基因依赖于可用于临床的蛋白质平衡网络。典型的例子是多发性骨髓瘤（MM）对20S蛋白酶体抑制剂（如卡非佐米）的高度敏感性。然而，MM患者总是对这些药物产生耐药性。利用新一代shRNA平台，我们发现蛋白酶抑制因子，包括伴侣和应激反应调节因子，控制着对卡非佐米的反应。矛盾的是，19S蛋白酶体调节因子敲低诱导MM和非MM细胞对卡非佐米耐药。19S亚基敲低不影响carfilzomib靶向的20S亚基的活性，也不影响carfilzomib对20S亚基的抑制作用，提示可能存在其他机制，如保护性因子的选择性积累。在MM患者中，较低的19S水平预示着对卡非佐米治疗的反应减弱。总之，我们的研究结果表明，对网络重新布线的理解可以为开发新的联合疗法提供信息，以克服耐药性。DOI: http://dx.doi.org/10.7554/eLife.08153.001细胞有几种机制来去除已经损坏或不再需要的蛋白质。其中一种机制是由一种叫做蛋白酶体的大型蛋白质复合物完成的。阻断蛋白酶体的药物对所有细胞都是有毒的，一种叫做多发性骨髓瘤的血癌对这些“蛋白酶体抑制剂”特别敏感。然而，多发性骨髓瘤患者的肿瘤也可能对这些药物产生耐药性。Acosta-Alvear等人利用遗传方法确定了控制细胞对蛋白酶体抑制剂敏感性的因素。特别是，降低有助于蛋白质平衡的其他因素的水平会使细胞更加敏感。结合使用蛋白酶体抑制剂和针对这些其他因素的药物可能在对抗多发性骨髓瘤中有用。蛋白酶体复合体包含两种亚基：识别需要降解的蛋白质的调节亚基和降解蛋白质的催化亚基。Acosta-Alvear等人的研究结果揭示了这两种亚基水平的变化如何影响细胞对抑制剂的敏感性。正如预期的那样，降低催化亚基的水平使细胞更加敏感，但令人惊讶的是，降低调节亚基的水平使细胞对抑制剂产生抗性。对于这一自相矛盾的结果，一种可能的解释是，这些细胞中的蛋白酶体对某些蛋白质的降解效率较低，而这些蛋白质的积累可以保护细胞免受药物的侵害。Acosta-Alvear等人还发现，较低水平的调节亚基使多发性骨髓瘤患者对基于蛋白酶体抑制的治疗脱敏，这表明在细胞中进行的遗传筛选结果可以预测临床耐药机制，并指导未来治疗方法的发展，以提高患者的生存率。DOI: http://dx.doi.org/10.7554/eLife.08153.002
Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance. DOI: http://dx.doi.org/10.7554/eLife.08153.001 Cells have several mechanisms for removing proteins that have been damaged or are no longer needed. One of these mechanisms is carried out by a large protein complex called the proteasome. Drugs that block the proteasome are toxic to all cells, and a type of blood cancer called multiple myeloma is particularly sensitive to these ‘proteasome inhibitors’. However, tumors in patients with multiple myeloma can also become resistant to these drugs. Using a genetic approach, Acosta-Alvear et al. identified the factors that control the sensitivity of cells to proteasome inhibitors. In particular, reducing the levels of other factors that contribute to protein balance made the cells more sensitive. Using a combination of proteasome inhibitors and drugs that target these other factors could prove to be useful in the fight against multiple myeloma. The proteasome complex contains two types of subunits: regulatory subunits that recognize the proteins that need to be degraded, and catalytic subunits that degrade the proteins. The results of Acosta-Alvear et al. revealed how varying the levels of these two subunits influenced the sensitivity of cells to inhibitors. While decreasing the levels of catalytic subunits made the cells more sensitive, as expected, decreasing the level of regulatory subunits surprisingly made the cells resistant to the inhibitors. A possible explanation for this paradoxical result is that certain proteins are less effectively degraded by the proteasome in these cells, and that the buildup of these proteins protects the cells against the drugs. Acosta-Alvear et al. also found that lower levels of regulatory subunits desensitized multiple myeloma patients to therapy based on proteasome inhibition, suggesting that results from the genetic screen carried out in cells can predict clinical resistance mechanisms and guide the development of future therapies to increase patient survival. DOI: http://dx.doi.org/10.7554/eLife.08153.002