Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia.
Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia.
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在急性淋巴细胞白血病中，含瓣膜蛋白/p97作为新型治疗靶标。
DOI：
10.1016/j.neo.2017.08.001
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Koeffler HP
中科院分区：
文献类型：
--
作者：
Gugliotta G;Sudo M;Cao Q;Lin DC;Sun H;Takao S;Le Moigne R;Rolfe M;Gery S;Müschen M;Cavo M;Koeffler HP
B 急性淋巴细胞白血病（B - ALL）细胞对内质网（ER）应激格外敏感。最近有研究表明，抑制p97可在实体瘤和多发性骨髓瘤中诱导内质网应激，进而导致细胞死亡。我们探究了一种新型口服p97抑制剂（CB - 5083；Cleave生物科学公司）在B - ALL中的作用。CB - 5083能显著降低10种人类B - ALL细胞系的活力，这些细胞系携带儿童和成人B - ALL中最常见的融合基因，其半数抑制浓度（IC50）范围为0.34至0.76微摩尔/升。此外，CB - 5083显著减少了OP1和NALM6细胞的集落形成。在BALL1和OP1细胞中，CB - 5083可早期且强烈地诱导细胞凋亡，同时多聚（ADP - 核糖）聚合酶（PARP）大量裂解。CB - 5083诱导内质网应激，具体表现为：1）伴侣蛋白（葡萄糖调节蛋白78（GRP78）、葡萄糖调节蛋白94（GRP94）、蛋白二硫键异构酶（PDI）、DnaJ热休克蛋白家族（Hsp40）成员C3（DNAJC3）和DnaJ热休克蛋白家族（Hsp40）成员B9（DNAJB9））显著表达；2）通过X盒结合蛋白1（XBP1）的剪接证明，肌醇需要酶1α（IRE1 - α）激活增加；3）蛋白激酶R样内质网激酶（PERK）激活，导致CCAAT增强子结合蛋白同源蛋白（CHOP）及其下游基因显著过表达。CB - 5083在GRP78基因敲除（GRP78−/−）、GRP94基因敲除（GRP94−/−）和XBP1基因敲除（XBP1−/−）细胞中也降低了细胞活力，这表明这些蛋白单独而言并非CB - 5083发挥活性所绝对必需的。此外，我们发现XBP1缺失（XBP1−/−）会增加对CB - 5083的敏感性，由此提出假设，即XBP1剪接可能通过减轻内质网应激来对抗CB - 5083的活性。最后，长春新碱与CB - 5083在BALL1和OP1细胞中具有协同作用。总之，使用CB - 5083靶向p97是一种有前景的新型治疗方法，值得在B - ALL中进一步评估。
B acute lymphoblastic leukemia (B-ALL) cells are distinctively vulnerable to endoplasmic reticulum (ER) stress. Recently, inhibition of p97 was shown to induce ER stress and subsequently cell death in solid tumors and in multiple myeloma. We investigated the role of a novel, orally available, p97 inhibitor (CB-5083; Cleave Biosciences) in B-ALL. CB-5083 induced a significant reduction in viability in 10 human B-ALL cell lines, harboring the most common fusion-genes involved in pediatric and adult B-ALL, with IC50s ranging from 0.34 to 0.76 μM. Moreover, CB-5083 significantly reduced the colony formation of OP1 and NALM6 cells. Early and strong induction of apoptosis was demonstrated in BALL1 and OP1 cells, together with a robust cleavage of PARP. CB-5083 induced ER stress, as documented through: 1) prominent expression of chaperones (GRP78, GRP94, PDI, DNAJC3, and DNAJB9); 2) increased activation of IRE1-alpha, as demonstrated by the splicing of XBP1; and 3) activation of PERK, which resulted in a significant overexpression of CHOP, and its downstream genes. CB-5083 reduced the viability also in GRP78−/−, GRP94−/−, and XBP1−/− cells, suggesting that none of these proteins alone was strictly required for CB-5083 activity. Moreover, we showed that the absence of XBP1 (XBP1−/−) increased the sensitivity to CB-5083, leading to the hypothesis that XBP1 splicing counteracts the activity of CB-5083, probably mitigating ER stress. Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 cells. In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.
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影响因子：
4
作者：
Meyer, Hemmo;Weihl, Conrad C.
通讯作者：
Weihl, Conrad C.
DOI：
10.1073/pnas.96.23.13180
发表时间：
1999-11-09
影响因子：
11.1
作者：
Iritani, BM;Eisenman, RN
通讯作者：
Eisenman, RN
影响因子：
7.3
作者：
Zhou, Han-Jie;Wang, Jinhai;Wustrow, David
通讯作者：
Wustrow, David
影响因子：
15.9
作者：
Hart, Lori S.;Cunningham, John T.;Koumenis, Constantinos
通讯作者：
Koumenis, Constantinos
影响因子：
11.2
作者：
Chou, Ting-Chao
通讯作者：
Chou, Ting-Chao