Assessment of the effect of sphingosine kinase inhibitors on apoptosis,unfolded protein response and autophagy of T-cell acute lymphoblastic leukemia cells; indications for novel therapeutics.
Assessment of the effect of sphingosine kinase inhibitors on apoptosis,unfolded protein response and autophagy of T-cell acute lymphoblastic leukemia cells; indications for novel therapeutics.
复制标题
DOI：
10.18632/oncotarget.2318
复制
发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Martelli AM
中科院分区：
文献类型：
--
作者：
Evangelisti C;Evangelisti C;Teti G;Chiarini F;Falconi M;Melchionda F;Pession A;Bertaina A;Locatelli F;McCubrey JA;Beak DJ;Bittman R;Pyne S;Pyne NJ;Martelli AM
1-磷酸鞘氨醇（S1 P）是一种生物活性脂质，由鞘氨醇磷酸化形成，并由鞘氨醇激酶1（SK 1）或鞘氨醇激酶2（SK 2）催化。鞘氨醇激酶在许多与癌症相关的信号通路中起着重要作用，这表明属于该信号网络的蛋白质代表了潜在的治疗靶点。在过去的几年里，在T细胞急性淋巴细胞白血病（T-ALL）的治疗方面已经取得了许多进展;然而，仍然需要新的和毒性较小的治疗方法，特别是对于复发和化疗耐药的患者。在这里，我们分析了SKi和罗马的治疗潜力，分别是鞘氨醇激酶1和2抑制剂和SK2选择性抑制剂。在我们的体外细胞模型中，当SKi诱导细胞凋亡时，罗马引发自噬性细胞死亡。SKi处理诱导Molt-4细胞中SK 1蛋白水平的增加，而它激活Jurkat和CEM-R细胞中的内质网（ER）应激/未折叠蛋白反应（UPR）途径，作为T-ALL细胞亚群中的保护机制。有趣的是，我们观察到SKi与经典化疗药物长春新碱的协同作用。此外，我们报道了SKi影响涉及细胞存活、增殖和应激反应的信号级联。这些发现表明SK 1或SK2代表了治疗T-ALL的潜在靶点。
Sphingosine 1-phosphate (S1P) is a bioactive lipid that is formed by the phosphorylation of sphingosine and catalysed by sphingosine kinase 1 (SK1) or sphingosine kinase 2 (SK2). Sphingosine kinases play a fundamental role in many signaling pathways associated with cancer, suggesting that proteins belonging to this signaling network represent potential therapeutic targets. Over the last years, many improvements have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL); however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of SKi and ROMe, a sphingosine kinase 1 and 2 inhibitor and SK2-selective inhibitor, respectively. While SKi induced apoptosis, ROMe initiated an autophagic cell death in our in vitro cell models. SKi treatment induced an increase in SK1 protein levels in Molt-4 cells, whereas it activated the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) pathway in Jurkat and CEM-R cells as protective mechanisms in a sub-population of T-ALL cells. Interestingly, we observed a synergistic effect of SKi with the classical chemotherapeutic drug vincristine. In addition, we reported that SKi affected signaling cascades implicated in survival, proliferation and stress response of cells. These findings indicate that SK1 or SK2 represent potential targets for treating T-ALL.
登录
查看更多内容
影响因子：
11.4
作者：
Buontempo, F.;Orsini, E.;Martelli, A. M.
通讯作者：
Martelli, A. M.
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
3.2
作者：
Johnson, KR;Johnson, KY;Obeid, LM
通讯作者：
Obeid, LM
影响因子：
11.4
作者：
Chiarini, F.;Del Sole, M.;Martelli, A. M.
通讯作者：
Martelli, A. M.
影响因子：
11.4
作者：
Evangelisti, C.;Ricci, F.;Martelli, A. M.
通讯作者：
Martelli, A. M.