Proteasome inhibition as a novel mechanism of the proapoptotic activity of γ-secretase inhibitor I in cutaneous T-cell lymphoma
Proteasome inhibition as a novel mechanism of the proapoptotic activity of γ-secretase inhibitor I in cutaneous T-cell lymphoma
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DOI：
10.1111/bjd.12071
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发表时间：
2013-03-01
影响因子：
10.3
通讯作者：
Gniadecki, R.
中科院分区：
文献类型：
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作者：
Biskup, E.;Kamstrup, M. R.;Gniadecki, R.
背景我们先前发现Notch 1在皮肤T细胞淋巴瘤（CTCL）的恶性T细胞上表达，并且是CTCL细胞系存活所必需的。Notch可被γ-分泌酶抑制剂（gamma-secretase inhibitors，GSIs）抑制，但不同GSIs诱导CTCL细胞凋亡的能力差异很大。目的研究GSI-I在抑制Notch的同时，是否通过抑制蛋白酶体诱导CTCL细胞凋亡，因为GSI-I与蛋白酶体抑制剂MG-132结构相似。（MyLa、SeAx、JK、Mac 1和Mac 2a）用GSI-I和两种其他蛋白酶体抑制剂（MG-132和硼替佐米）处理。测量了对细胞活力、细胞凋亡和蛋白酶体活性的影响，以及对促生存、核因子kappa B（NF-kappa B）途径的影响。结果在CTCL中，GSI-I具有蛋白酶体阻断活性，其效力与蛋白酶体抑制剂MG-132和硼替佐米相当。蛋白酶体抑制是GSI-I诱导细胞死亡的主要机制，因为已知可逆转MG-132作用的化合物Tiron可恢复蛋白酶体活性并在很大程度上消除GSI-I的细胞毒性作用。虽然NF-κ B的失活是蛋白酶体抑制剂的重要作用机制，但我们证实了NF-κ B的明显活化。此外，我们表明，虽然肿瘤抑制蛋白p53在蛋白酶体抑制过程中被诱导，但它对CTCL细胞凋亡是不利的，因为SeAx细胞和HuT-78细胞都具有减弱凋亡能力的p53突变，而HuT-78细胞具有缺失的p53基因，GSI-1000显示了强有力的凋亡反应。结论I代表了一种具有双重作用机制的有趣药物，包括抑制Notch和蛋白酶体。
Background We have previously discovered that Notch1 is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL), and is required for survival of CTCL cell lines. Notch can be inhibited by gamma-secretase inhibitors (GSIs), which differ widely in their ability to induce apoptosis in CTCL.Objectives To investigate whether GSI-I, in addition to inhibiting Notch, induces apoptosis in CTCL by proteasome inhibition, as GSI-I is very potent and has structural similarity to the proteasome inhibitor MG-132.Methods Cell lines derived from CTCL (MyLa, SeAx, JK, Mac1 and Mac2a) were treated with GSI-I and two other proteasome inhibitors (MG-132 and bortezomib). The effects on cell viability, apoptosis and proteasome activity were measured, as was the impact on the prosurvival, nuclear factor kappa B (NF-kappa B) pathway.Results In CTCL, GSI-I had proteasome-blocking activity with a potency comparable to the proteasome inhibitors MG-132 and bortezomib. Proteasome inhibition was the main mechanism responsible for GSI-I-induced cell death, as tiron, a compound known to reverse the effect of MG-132, restored proteasome activity and largely abrogated the cytotoxic effect of GSI-I. Although inactivation of NF-kappa B is an important mechanism of action for proteasome inhibitors, we demonstrated an apparent activation of NF-kappa B. Furthermore, we showed that while the tumour suppressor protein p53 was induced during proteasome inhibition, it was dispensable for CTCL apoptosis, as both SeAx cells, which harbour p53 mutations that attenuate the apoptotic capacity, and HuT-78 cells, which have a deleted p53 gene, demonstrated potent apoptotic response.Conclusions GSI-I represents an interesting drug with a dual mechanism of action comprising inhibition of both Notch and the proteasome.