title: The clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition, oxidative stress, and interference with Notch1 signaling.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.|Faculty of Chemistry and Pharmacy, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: De Ford
authors.affiliation: Faculty of Chemistry and Pharmacy, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Heidersdorf
authors.affiliation: Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.|Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Haun
authors.affiliation: Escuela de Química and CIPRONA, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: R
authors.initials: R
authors.lastname: Murillo
authors.affiliation: Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.|Institut für Biochemie, Albert Ludwigs University, Freiburg, Germany.
authors.forename: T
authors.identifier: http://orcid.org/0000-0002-0813-7883
authors.initials: T
authors.lastname: Friedrich
authors.affiliation: Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.|Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Freiburg, Germany.|Centre for Biological Signaling Studies (BIOSS), Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Borner
authors.affiliation: Department of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.|Faculty of Chemistry and Pharmacy, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Merfort
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D045785:Diterpenes, Clerodane; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
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