HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia
HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia
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DOI：
10.1002/ijc.32383
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发表时间：
2019-12-01
影响因子：
6.4
通讯作者：
Trentin, Livio
中科院分区：
文献类型：
--
作者：
Frezzato, Federica;Raggi, Flavia;Trentin, Livio
考虑到70 kDa的热休克蛋白（HSP 70）在癌症中发挥的作用，我们在慢性淋巴细胞白血病（CLL）中描述了这种蛋白质及其主要调节因子热休克因子1（HSF 1）。我们发现HSP 70和HSF 1在CLL患者中均过表达，与预后不良相关，并且异常定位于白血病B细胞核。这两种蛋白彼此严格相关，并且在对体内治疗方案有反应的患者中它们的水平一致地降低。HSP 70和HSF 1抑制剂在体外可诱导CLL B细胞凋亡，且呈剂量依赖性。考虑到HSF 1受到属于大鼠肉瘤（RAS）触发途径的激酶的精细调节，我们受益于之前在CLL患者中进行的旨在评估关键信号蛋白激活/表达的蛋白质组学研究。我们发现，显示高水平HSP 70的患者也表达高Akt-Ser 473，从而激活HSF 1。抑制激活AKT的PI 3 K，减少HSF 1和HSP 70的表达。相比之下，HSP 70低的患者显示出MEK 1/2和ERK 1/2的高活化，已知其负调节HSF 1。这些数据表明，HSP 70的表达是通过激活RAS调节的途径调节HSF 1活性来调节的，并表明HSP 70/HSF 1相互作用是抗白血病治疗的一个有趣的靶点。最后，抑制激活AKT的PI 3 K，减少HSF 1和HSP 70的表达。
Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.