Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells
Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells
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DOI：
10.1016/j.bbrc.2020.02.165
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发表时间：
2020-05-14
影响因子：
3.1
通讯作者：
Murate, Takahsi
中科院分区：
文献类型：
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作者：
Inoue, Chisato;Sobue, Sayaka;Murate, Takahsi
T315 I突变是包括伊马替尼在内的BCR/ABL激酶抑制剂耐药中最严重的一种，仅对泊那替尼（PNT）有反应，见于慢性粒细胞白血病（CML）和Ph + ALL患者。然而，需要新的策略来减少PNT的危及生命的不良反应，包括缺血性心血管疾病。我们研究了PNT诱导的细胞毒性对T315 I（+）Ph + ALL细胞系TccY/Sr的机制。PNT诱导细胞凋亡（增加亚G1细胞，切割半胱天冬酶3和PARP），并抑制MCL 1，细胞周期蛋白D2和c-myc的蛋白表达，这被蛋白酶体抑制剂MG 132逆转，表明PNT增强了蛋白酶体降解。在BCL 2家族抑制剂中，MCL 1抑制剂（maritoclax和AZD 5991）强烈诱导细胞死亡，显示TccY/Sr细胞的MCL 1依赖性存活。在T315 I（+）MEGA 2/STIR细胞中，PNT可降低MCL 1和c-myc的表达。PNT抑制PI 3 K活化，随后抑制AKT和GSK 3去磷酸化。PI 3 K/AKT抑制剂模拟PNT，表明PI 3 K/AKT信号传导对于TccY/Sr细胞的存活是重要的。此外，GSK 3抑制剂（SB 216763）减少了CNT诱导的细胞毒性和c-myc和MCL 1的降解。AZD 5991与PNT、抗癌药物和venetoclax（BCL 2抑制剂）显示出协同作用，表明MCL 1抑制剂单独或联合使用可作为Ph +白血病患者的未来临床选择。(C)2020爱思唯尔公司All rights reserved.
T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic cardiovascular disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-myc, which were reversed by a proteasome inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by AKT inhibition and GSK3 dephosphorylation. PI3K/AKT inhibitors mimicked PNT, suggesting that PI3K/AKT signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients. (C) 2020 Elsevier Inc. All rights reserved.