XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB.
XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB.
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DOI：
10.1016/j.tranon.2021.101114
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发表时间：
2021-08
影响因子：
5
通讯作者：
Weiser DA
中科院分区：
文献类型：
--
作者：
Galinski B;Luxemburg M;Landesman Y;Pawel B;Johnson KJ;Master SR;Freeman KW;Loeb DM;Hébert JM;Weiser DA
XPO1 在高危神经母细胞瘤中含量过多，与生存率低相关。神经母细胞瘤细胞对 selinexor 的 XPO1 抑制敏感。使用 selinexor 会导致 IkB 核滞留，从而降低 NF-kB 活性。 Selinexor 和硼替佐米通过促进细胞凋亡发挥协同作用。协同作用部分是通过 NF-kB 活性的 IkB 调节介导的。在成人的许多癌症类型中，核到细胞质转运蛋白 Exportin-1 (XPO1) 的上调与不良预后和对 selinexor（FDA 批准的 XPO1 抑制剂）的反应性相关。类似的数据也在儿童癌症中出现，selinexor 正在早期临床研究中对其进行评估。通过对高危神经母细胞瘤患者的原发性肿瘤材料进行蛋白质组学分析，以及对独立队列进行基因表达分析，我们证明 XPO1 过度表达与患者预后不良相关。神经母细胞瘤细胞系对低纳摩尔范围的 selinexor 也敏感。基于这些发现和硼替佐米（一种蛋白酶体抑制剂）可阻止 XPO1 货物蛋白降解的知识，我们假设 selinexor 和硼替佐米的联合治疗将协同抑制神经母细胞瘤细胞增殖。我们观察到，selinexor 促进 IkB 的核保留，并且硼替佐米增强了 selinexor 诱导细胞周期停滞和细胞凋亡导致的细胞死亡的能力。通过 siRNA 敲低 IkB，这种协同作用被消除。 Selinexor 和硼替佐米在体外联合使用的协同效应为进一步研究这种联合治疗高危神经母细胞瘤患者提供了理论基础。
XPO1 is overabundant in high-risk neuroblastoma and correlates with poor survival. Neuroblastoma cells are sensitive to XPO1 inhibition with selinexor. Use of selinexor results in nuclear retention of IkB, diminishing NF-kB activity. Selinexor and bortezomib act synergistically through promotion of apoptosis. Synergy is mediated in part, through IkB regulation of NF-kB activity. Across many cancer types in adults, upregulation of the nuclear-to-cytoplasmic transport protein Exportin-1 (XPO1) correlates with poor outcome and responsiveness to selinexor, an FDA-approved XPO1 inhibitor. Similar data are emerging in childhood cancers, for which selinexor is being evaluated in early phase clinical studies. Using proteomic profiling of primary tumor material from patients with high-risk neuroblastoma, as well as gene expression profiling from independent cohorts, we have demonstrated that XPO1 overexpression correlates with poor patient prognosis. Neuroblastoma cell lines are also sensitive to selinexor in the low nanomolar range. Based on these findings and knowledge that bortezomib, a proteasome inhibitor, blocks degradation of XPO1 cargo proteins, we hypothesized that combination treatment with selinexor and bortezomib would synergistically inhibit neuroblastoma cellular proliferation. We observed that selinexor promoted nuclear retention of IkB and that bortezomib augmented the ability of selinexor to induce cell-cycle arrest and cell death by apoptosis. This synergy was abrogated through siRNA knockdown of IkB. The synergistic effect of combining selinexor and bortezomib in vitro provides rationale for further investigation of this combination treatment for patients with high-risk neuroblastoma.
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影响因子：
2.4
作者：
Escobar, MA;Grosfeld, JL;Rescorla, FJ
通讯作者：
Rescorla, FJ
影响因子：
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作者：
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通讯作者：
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作者：
Bahlis, Nizar J.;Sutherland, Heather;Chen, Christine
通讯作者：
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作者：
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Jagannath, Sundar
DOI：
10.1093/jnci/djj309
发表时间：
2006-08-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Brignole, Chiara;Marimpietri, Danilo;Ponzoni, Mirco
通讯作者：
Ponzoni, Mirco