Notch3 contributes to T-cell leukemia growth via regulation of the unfolded protein response
Open Access
- 18 October 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogenesis
- Vol. 9 (10), 1-16
- https://doi.org/10.1038/s41389-020-00279-7
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.Keywords
This publication has 64 references indexed in Scilit:
- The Anti-Cancer IgM Monoclonal Antibody PAT-SM6 Binds with High Avidity to the Unfolded Protein Response Regulator GRP78PLOS ONE, 2012
- Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myelomaBlood, 2012
- The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small moleculeProceedings of the National Academy of Sciences of the United States of America, 2012
- The Unfolded Protein Response: From Stress Pathway to Homeostatic RegulationScience, 2011
- AMPK and Akt Determine Apoptotic Cell Death following Perturbations of One-Carbon Metabolism by Regulating ER Stress in Acute Lymphoblastic LeukemiaMolecular Cancer Therapeutics, 2011
- Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myelomaBlood, 2011
- The Pin 1 inhibitor juglone attenuates kidney fibrogenesis via Pin 1-independent mechanisms in the unilateral ureteral occlusion modelFibrogenesis & Tissue Repair, 2010
- Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2EMBO Reports, 2008
- FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitorsThe Journal of Experimental Medicine, 2007
- Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic LeukemiaScience, 2004