title: A calpain-cleaved fragment of β-catenin promotes BCRABL1+ cell survival evoked by autophagy induction in response to imatinib.
abstract: Autophagy protects chronic myeloid leukemia stem cells from tyrosine kinase inhibitors hence supporting the disease persistence under therapy. However, the signals involved in autophagy regulation relative to BCR-ABL1 are still elusive. The autophagic flux proceeding from the inhibition of BCR-ABL1 tyrosine kinase represents a regulatory mechanism of β-catenin stability through events encompassing the activation of calpain, which targets β-catenin for proteasome-independent degradation. Accordingly, its inactivation may contribute to induce autophagy and autophagy induction may, in turn, promote β-catenin autolysosomal degradation to originate a regulatory loop where β-catenin plays a central role in cell decision between life and death. Here we proved that the cytoplasmic accumulation of β-catenin driven by up-regulation of its antagonist Chibby1 is a component of autophagy induction in response to imatinib in BCR-ABL1+ cells opposing the apoptotic death. It is contingent upon ER stress and elevation of free Ca(2+) cytosolic concentration and results in the calpain cleavage into a 28kDa fragment implicated in β-catenin proteasome-independent degradation. More important for BCR-ABL1+ cell survival and proliferation following IM treatment, might be the calpain-mediated cleavage of β-catenin accumulated within the cytoplasmic compartment into a 75kDa fragment, still owning TCF-dependent transcriptional activity. Such a β-catenin fragment might be crucial for BCR-ABL1+ cell survival following the fusion protein TK inhibition.
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy. Electronic address: mancini_manu@yahoo.com.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Leo
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Campi
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Zazzeroni
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gugliotta
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale DIMES, Istituto di Ematologia "L. e A. Seràgnoli," University of Bologna, Medical School, via Massarenti, 940138 Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C473750:CBY1 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; D051176:beta Catenin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D002154:Calpain; D002118:Calcium
keywords: Autophagy; Chibby1; Chronic myeloid leukemia; Imatinib; β-Catenin