Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA
Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA
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DOI：
10.1182/blood-2007-12-130823
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发表时间：
2008-10-01
期刊：
影响因子：
20.3
通讯作者：
McConkey, David J.
中科院分区：
文献类型：
--
作者：
Nawrocki, Steffan T.;Carew, Jennifer S.;McConkey, David J.
组蛋白去乙酰化酶抑制剂SAHA通过破坏蛋白酶体抑制剂硼替佐米（BZ）诱导的攻击体形成来增强由BZ刺激的细胞死亡。在这里，我们报告说，Myc调节多发性骨髓瘤（MM）细胞的敏感性BZ + SAHA诱导的细胞死亡。在MM细胞中，Myc表达与细胞内ER含量、蛋白质合成速率、攻击基因组阳性细胞百分比以及对BZ + SAHA诱导的细胞死亡的敏感性直接相关。因此，Myc基因敲减显著降低了MM细胞对BZ + SAHA介导的凋亡的敏感性。此外，Myc的激活足以引起攻击性基因组的形成，从而对BZ + SAHA敏感，这些反应需要从头蛋白质合成。BZ + SAHA介导的细胞凋亡刺激包括诱导促细胞凋亡的仅BH 3蛋白Noxa以及内质网应激、钙稳态的破坏和半胱天冬酶-4的活化。最后，敲除研究表明，caspase-4和Noxa在Myc驱动的对BZ + SAHA诱导的细胞凋亡的敏感性中起重要作用。总的来说，我们的研究结果建立了Myc活性，蛋白质合成的调节，HDAC 6表达和侵略形成，Noxa的诱导，以及对BZ + SAHA诱导的细胞凋亡的敏感性之间的机制联系。这些数据表明，Myc活性升高的MM患者可能对BZ + SAHA联合治疗特别敏感。
The histone deacetylase inhibitor SAHA enhances cell death stimulated by the proteasome inhibitor bortezomib (BZ) by disrupting BZ-induced aggresome formation. Here we report that Myc regulates the sensitivity of multiple myeloma ( MM) cells to BZ + SAHA-induced cell death. In MM cells, Myc expression directly correlated with intracellular ER content, protein synthesis rates, the percentage of aggresome-positive cells, and the sensitivity to BZ + SAHA-induced cell death. Accordingly, Myc knockdown markedly reduced the sensitivity of MM cells to BZ + SAHA-mediated apoptosis. Furthermore, activation of Myc was sufficient to provoke aggresome formation and thus sensitivity to BZ + SAHA, and these responses required de novo protein synthesis. BZ + SAHA-mediated stimulation of apoptosis includes the induction of the proapoptotic BH3-only protein Noxa as well as endoplasmic reticular stress, a disruption of calcium homeostasis, and activation of capase-4. Finally, knockdown studies demonstrated that both caspase-4 and Noxa play significant roles in Myc-driven sensitivity to BZ + SAHA-induced apoptosis. Collectively, our results establish a mechanistic link between Myc activity, regulation of protein synthesis, increases in HDAC6 expression and aggresome formation, induction of Noxa, and sensitivity to BZ + SAHA-induced apoptosis. These data suggest that MM patients with elevated Myc activity may be particularly sensitive to the BZ + SAHA combination.