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dc.contributor.authorVisa Pretel, Anna
dc.contributor.authorAlza, Lía
dc.contributor.authorCantí Nicolás, Carles
dc.contributor.authorHerreros Danés, Judit
dc.description.abstractMibefradil and NNC-55-0396, tetralol derivatives with a proven ability to block T-type calcium channels in excitable cells, reduce cancer cell viability in vitro, causing cell death. Furthermore, they reduce tumor growth in preclinical models of Glioblastoma multiforme (GBM), a brain tumor of poor prognosis. Here we found that GBM cells treated with cytotoxic concentrations of NNC-55-0396 paradoxically increased cytosolic calcium levels through the activation of inositol triphosphate receptors (IP3R) and ER stress. We used pharmacological inhibitors and gene silencing to dissect the cell death pathway stimulated by NNC-55-0396 in GBM cell lines and biopsy-derived cultures. Calcium chelation or IP3R inhibition prevented NNC-55-0396-mediated cytotoxicity, indicating that ER calcium efflux is the cause of cell death. Upstream of calcium mobilization, NNC-55-0396 activated the IRE1α arm of the Unfolded Protein Response (UPR) resulting in the nuclear translocation of pro-apoptotic CHOP. Consistent with these findings, silencing IRE1α or JNK1 rescued the cell death elicited by NNC-55-0396. Therefore, we demonstrate that activation of IRE1α and calcium signaling accounts for the cytotoxicity of NNC-55-0396 in GBM cells. The delineation of the signaling pathway that mediates the abrupt cell death triggered by this compound can help the development of new therapies for GBM.
dc.description.sponsorshipWe are grateful to Dr. S. Shaikh for help with initial calcium experiments and to Dr. E. Vilaprinyó for statistical analysis. We acknowledge the technical support of D. Argilés and assistance from the personnel of the Cell Culture and the Flow Cytometry Services of IRBLleida/UdL. This work was funded by grants from the Spanish Ministry of Science and Innovation/FEDER “Una manera de hacer Europa” (Retos Program, number RTI2018-094739-B-I00 to JH & CC) and Fundació La Marató de TV3 (number 235/C/2019 to CC). AV was funded by UdL, IRBLleida-Diputació de Lleida and La Marató de TV3. LA is a recipient of an FI-AGAUR predoctoral fellowship. Work supported by IRBLleida Biobank (B.0000682) and Plataforma Biobancos PT17/0015/0027/
dc.relation.isformatofReproducció del document publicat a:
dc.relation.ispartofBiomedicine & Pharmacotherapy, 2022, vol. 149, p. 112881
dc.rightscc-by-nc-nd (c) Authors, 2022
dc.subjectER stress
dc.subjectCell death
dc.titleTetralol derivative NNC-55-0396 induces glioblastoma cell death by activating IRE1α, JNK1 and calcium signaling

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cc-by-nc-nd (c) Authors, 2022
Except where otherwise noted, this item's license is described as cc-by-nc-nd (c) Authors, 2022