The clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition, oxidative stress, and interference with Notch1 signaling.
The clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition, oxidative stress, and interference with Notch1 signaling.
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DOI：
10.1038/cddis.2015.413
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发表时间：
2016-01-28
影响因子：
9
通讯作者：
Merfort I
中科院分区：
文献类型：
--
作者：
De Ford C;Heidersdorf B;Haun F;Murillo R;Friedrich T;Borner C;Merfort I
t细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液系统恶性肿瘤，优先影响儿童和青少年。超过50%的人类t - all具有Notch1的激活突变。克罗丹二萜酪蛋白J （CJ）是一种天然产物，可抑制肌内质网钙atp酶（SERCA）泵并诱导白血病细胞死亡，但其细胞毒性的分子机制尚不清楚。本研究表明，由于SERCA泵抑制，CJ通过内在信号通路诱导内质网钙池消耗、氧化应激和细胞凋亡。此外，Notch1信号在Notch1 hd结构域发生自激活突变的T-ALL细胞中减少，但在不依赖Notch1信号的细胞中则不减少。CJ也引起了NF-κB的轻微激活，与这一观点一致的是，CJ和NF-κB抑制剂parthenolide （Pt）联合治疗导致T-ALL细胞显著的协同细胞死亡。总之，我们的数据支持这样一个概念，即抑制SERCA泵可能是治疗hd结构域突变Notch1受体的T-ALL的一种新策略，并且使用NF-κB抑制剂parthenolide进行额外治疗可能具有进一步的治疗效果。
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that preferentially affects children and adolescents. Over 50% of human T-ALLs possess activating mutations of Notch1. The clerodane diterpene casearin J (CJ) is a natural product that inhibits the sarcoendoplasmatic reticulum calcium ATPase (SERCA) pump and induces cell death in leukemia cells, but the molecular mechanism of cytotoxicity remains poorly understood. Here we show that owing to SERCA pump inhibition, CJ induces depletion of the endoplasmic reticulum calcium pools, oxidative stress, and apoptosis via the intrinsic signaling pathway. Moreover, Notch1 signaling is reduced in T-ALL cells with auto-activating mutations in the HD-domain of Notch1, but not in cells that do not depend on Notch1 signaling. CJ also provoked a slight activation of NF-κB, and consistent with this notion a combined treatment of CJ and the NF-κB inhibitor parthenolide (Pt) led to a remarkable synergistic cell death in T-ALL cells. Altogether, our data support the concept that inhibition of the SERCA pump may be a novel strategy for the treatment of T-ALL with HD-domain-mutant Notch1 receptors and that additional treatment with the NF-κB inhibitor parthenolide may have further therapeutic benefits.