Abstract
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.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor resulting from the malignant transformation of T-cell progenitors
Tunicamycin decreased the proportion of viable cells by increasing cell death, as we observed an increase in the pro-apoptotic cleaved form of poly ADPribose polymerase PARP (C-PARP) in all T-ALLs analyzed (Fig. 1b)
The therapeutic potential of targeting Unfolded protein response (UPR) signaling in cancer could involve two main approaches: 1. inhibition of UPR to eradicate tumors that are strongly dependent on an activated UPR for their survival in unfavorable conditions or 2. induction of a severe endoplasmic reticulum (ER) stress by the accumulation of misfolded protein in the ER in order to overload restoration ability of tumor cells with compromised UPR or to hyper activate the UPR to kill cells through pro-apoptotic UPR signaling[46]
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor resulting from the malignant transformation of T-cell progenitors. Notch[1] activity in about 60% of cases, due to activating Notch[1] mutations or alterations in the FBXW7 gene[2,3]. By screening primary T-ALL tumors and orthotopic patientderived xenograft models, activating mutations of Notch[3] have been recently identified, detectable in the absence of an activated Notch[14]. Since constitutive activation of the Notch signaling pathway confers to the leukemic cells a strong growth advantage, the Notch therapeutic targeting has assumed a considerable clinical relevance, especially for patients refractory to chemotherapy[5]. The gamma-secretase inhibitors (GSIs) treatment, which blocks cleavage of Notch receptors, exhibits significant gastrointestinal toxicity, mainly due to the simultaneous inhibition of Notch[1] and Notch[2] signaling in gut epithelial stem cells[6]
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