A calpain-cleaved fragment of beta-catenin promotes BCRABL1+cell survival evoked by autophagy induction in response to imatinib

作者：Mancini Manuela^*; Leo Elisa; Campi Virginia; Castagnetti Fausto; Zazzeroni Luca; Gugliotta Gabriele; Santucci Maria Alessandra; Martinelli Giovanni

来源：Cellular Signalling, 2014, 26(8): 1690-1697.

DOI：10.1016/j.cellsig.2014.04.010

• Chronic myeloid leukemia
• Imatinib
• beta-Catenin
• Chibby1
• Autophagy

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 beta-catenin stability through events encompassing the activation of calpain, which targets beta-catenin for proteasome-independent degradation. Accordingly, its inactivation may contribute to induce autophagy and autophagy induction may, in turn, promote beta-catenin autolysosomal degradation to originate a regulatory loop where beta-catenin plays a central role in cell decision between life and death. Here we proved that the cytoplasmic accumulation of beta-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 Ca2+ cytosolic concentration and results in the calpain cleavage into a 28 kDa fragment implicated in beta-catenin proteasome-independent degradation. More important for BCR-ABL1 + cell survival and proliferation following IM treatment, might be the calpain-mediated cleavage of beta-catenin accumulated within the cytoplasmic compartment into a 75 kDa fragment still owning TCF-dependent transcriptional activity. Such a beta-catenin fragment might be crucial for BCR-ABL1 + cell survival following the fusion protein TK inhibition.

• 出版日期2014-8