Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.
Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.
复制标题
DOI：
10.3389/fcvm.2018.00125
复制
发表时间：
2018
影响因子：
3.6
通讯作者：
Le NT
中科院分区：
文献类型：
--
作者：
Paez-Mayorga J;Chen AL;Kotla S;Tao Y;Abe RJ;He ED;Danysh BP;Hofmann MC;Le NT
泊那替尼是一种多靶向第三代酪氨酸激酶抑制剂（TKI），用于治疗携带Abelson（Abl）-断点簇区（Bcr）T315 I突变的慢性粒细胞白血病（CML）患者。尽管泊那替尼具有极好的临床疗效，但它会引发严重的血管不良事件（VAE），从而显著限制其治疗潜力。在血管内皮细胞（EC）上，泊那替尼促进EC功能障碍和凋亡，并抑制血管生成。此外，已表明泊那替尼介导的抗血管生成作用通过抑制血管内皮生长因子受体2（VEGFR 2）在全身性和肺动脉高压中发挥部分作用。尽管泊那替尼相关VAE已被充分记录，但其病因仍在很大程度上未知，因此难以有效对抗治疗相关不良反应。因此，更好地了解泊那替尼介导VAE的机制至关重要。在用泊那替尼处理的培养的人主动脉内皮细胞（HAEC）中，我们发现核因子NF-κ B/p65磷酸化和NF-κ B活性、炎症基因表达、细胞通透性和细胞凋亡增加。从机制上讲，即使在其上游激酶丝裂原活化蛋白激酶激酶5α（CA-MEK 5 α）激活的情况下，Ponatinib也可消除细胞外信号调节激酶5（ERK 5）的转录活性。泊那替尼还降低了ERK 5应答基因的表达，如Krüppel样因子2/4（klf 2/4）和eNOS。由于ERK 5 SUMO化抵消其转录活性，我们检查了泊那替尼对ERK 5 SUMO化的影响，发现泊那替尼增加了ERK 5 SUMO化。我们还发现，当ERK 5 SUMO化被内源性或外源性抑制时，Ponatibib介导的炎症基因表达增加和抗炎基因表达减少被逆转。总的来说，我们提出了一种新的机制，通过这种机制，泊那替尼上调内皮细胞ERK 5 SUMO化，并将EC转变为炎症表型，破坏血管稳态。
Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5α (CA-MEK5α). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.
登录
查看更多内容
影响因子：
20.1
作者：
Heo KS;Chang E;Le NT;Cushman H;Yeh ET;Fujiwara K;Abe J
通讯作者：
Abe J
费城染色体在白血病发生中的作用
影响因子：
--
作者：
Kang ZJ;Liu YF;Xu LZ;Long ZJ;Huang D;Yang Y;Liu B;Feng JX;Pan YJ;Yan JS;Liu Q
通讯作者：
Liu Q
影响因子：
37.8
作者：
Cameron SJ;Ture SK;Mickelsen D;Chakrabarti E;Modjeski KL;McNitt S;Seaberry M;Field DJ;Le NT;Abe J;Morrell CN
通讯作者：
Morrell CN
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
3.5
作者：
Cameron, SJ;Itoh, S;Abe, J
通讯作者：
Abe, J