title: Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation.
abstract: The calcineurin (Cn)-nuclear factor of activated T cells signaling pathway is critically involved in many aspects of normal T-cell physiology; however, its direct implication in leukemogenesis is still ill-defined. Glycogen synthase kinase-3β (GSK-3β) has recently been reported to interact with Cn in neuronal cells and is implicated in MLL leukemia. Our biochemical studies clearly demonstrated that Cn was able to interact with GSK-3β in T-cell acute lymphoblastic leukemia (T-ALL) cells, and that this interaction was direct, leading to an increased catalytic activity of GSK-3β, possibly through autophosphorylation of Y216. Sensitivity to GSK-3 inhibitor treatment correlated with altered GSK-3β phosphorylation and was more prominent in T-ALL with Pre/Pro immunophenotype. In addition, dual Cn and GSK-3 inhibitor treatment in T-ALL cells promoted sensitization to apoptosis through proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP). Consistently, resistance to drug treatments in primary samples was strongly associated with higher XIAP protein levels. Finally, we showed that dual Cn and GSK-3 inhibitor treatment in vitro and in vivo is effective against available models of T-ALL, indicating an insofar untapped therapeutic opportunity.
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Tosello
authors.affiliation: Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita' di Padova, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bordin
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY, USA.|Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: J
authors.identifier: http://orcid.org/0000-0003-3629-4330
authors.initials: J
authors.lastname: Yu
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Agnusdei
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Indraccolo
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università di Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.|Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita' di Padova, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Amadori
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.|Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita' di Padova, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Piovan
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019703:Calcineurin / Q000737:chemistry* / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin