Giuli Maria Valeria, Diluvio Giulia, Giuliani Eugenia, Franciosa Giulia, Di Magno Laura, Pignataro Maria Gemma, Tottone Luca, Nicoletti Carmine, Besharat Zein Mersini, Peruzzi Giovanna, Pelullo Maria, Palermo Rocco, Canettieri Gianluca, Talora Claudio, d'Amati Giulia, Bellavia Diana, Screpanti Isabella, Checquolo Saula
Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
Oncogenesis. 2020 Oct 18;9(10):93. doi: 10.1038/s41389-020-00279-7.
Unfolded protein response (UPR) is a conserved adaptive response that tries to restore protein homeostasis after endoplasmic reticulum (ER) stress. Recent studies highlighted the role of UPR in acute leukemias and UPR targeting has been suggested as a therapeutic approach. Aberrant Notch signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), as downregulation of Notch activity negatively affects T-ALL cell survival, leading to the employment of Notch inhibitors in T-ALL therapy. Here we demonstrate that Notch3 is able to sustain UPR in T-ALL cells, as Notch3 silencing favored a Bip-dependent IRE1α inactivation under ER stress conditions, leading to increased apoptosis via upregulation of the ER stress cell death mediator CHOP. By using Juglone, a naturally occurring naphthoquinone acting as an anticancer agent, to decrease Notch3 expression and induce ER stress, we observed an increased ER stress-associated apoptosis. Altogether our results suggest that Notch3 inhibition may prevent leukemia cells from engaging a functional UPR needed to compensate the Juglone-mediated ER proteotoxic stress. Notably, in vivo administration of Juglone to human T-ALL xenotransplant models significantly reduced tumor growth, finally fostering the exploitation of Juglone-dependent Notch3 inhibition to perturb the ER stress/UPR signaling in Notch3-dependent T-ALL subsets.
未折叠蛋白反应（UPR）是一种保守的适应性反应，旨在在内质网（ER）应激后恢复蛋白质稳态。最近的研究突出了UPR在急性白血病中的作用，并有人提出将靶向UPR作为一种治疗方法。异常的Notch信号是T细胞急性淋巴细胞白血病（T-ALL）的一个共同特征，因为Notch活性的下调会对T-ALL细胞存活产生负面影响，从而导致在T-ALL治疗中使用Notch抑制剂。在此我们证明，Notch3能够维持T-ALL细胞中的UPR，因为在ER应激条件下，Notch3沉默有利于依赖Bip的IRE1α失活，通过上调ER应激细胞死亡介质CHOP导致凋亡增加。通过使用胡桃醌（一种天然存在的萘醌，用作抗癌剂）来降低Notch3表达并诱导ER应激，我们观察到ER应激相关凋亡增加。我们的结果总体表明，抑制Notch3可能会阻止白血病细胞进行功能性UPR，而这种UPR是补偿胡桃醌介导的ER蛋白毒性应激所必需的。值得注意的是，在人T-ALL异种移植模型中体内给予胡桃醌可显著降低肿瘤生长，最终促进利用依赖胡桃醌的Notch3抑制来扰乱Notch3依赖性T-ALL亚群中的ER应激/UPR信号。
