Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling
Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling
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DOI：
10.1038/leu.2013.349
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发表时间：
2014-03-01
期刊：
影响因子：
11.4
通讯作者：
Martelli, A. M.
中科院分区：
文献类型：
--
作者：
Buontempo, F.;Orsini, E.;Martelli, A. M.
组成性激活的酪蛋白激酶2（CK 2）信号传导是T细胞急性淋巴细胞白血病（T-ALL）的共同特征。CK 2磷酸化PTEN（磷酸酶和张力蛋白同源物）肿瘤抑制因子，导致PTEN稳定和功能失活。PTEN活性的下调对PI 3 K/Akt/mTOR信号传导有影响，这对T-ALL细胞存活具有根本重要性。这些观察结果为CK 2抑制剂在T-ALL治疗中的应用提供了令人信服的权重。在这里，我们分析了CX-4945的治疗潜力-一种新型的，高度特异性的，口服的，ATP竞争性CK 2 α抑制剂。我们发现CX-4945处理诱导T-ALL细胞系和患者T淋巴母细胞凋亡。CX-4945在白血病细胞中下调PI 3 K/Akt/mTOR信号传导。值得注意的是，CX-4945影响未折叠蛋白反应（UPR），如主要UPR调节剂GRP 78/BIP水平的显著降低所证明的，并通过ER应激/UPR细胞死亡介质IRE 1 α和CHOP的上调导致细胞凋亡。CX-4945对人T-ALL的皮下异种移植模型的体内给药显著延迟了肿瘤生长。我们的研究结果表明，通过CK 2抑制调节ER应激/UPR信号传导可用于诱导T-ALL细胞凋亡，CX-4945可能是对那些显示CK 2 α/PI 3 K/Akt/mTOR信号传导上调的T-ALL的有效治疗。
Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945-a novel, highly specific, orally available, ATP-competitive inhibitor of CK2 alpha. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1 alpha and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2 alpha/PI3K/Akt/mTOR signaling.