1. The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells.
- Author
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Tomasella A, Picco R, Ciotti S, Sgorbissa A, Bianchi E, Manfredini R, Benedetti F, Trimarco V, Frezzato F, Trentin L, Semenzato G, Delia D, and Brancolini C
- Subjects
- Apoptosis drug effects, Ataxia Telangiectasia Mutated Proteins metabolism, Bortezomib pharmacology, Cell Line, Tumor, Humans, Proteasome Endopeptidase Complex drug effects, Antineoplastic Agents pharmacology, Ataxia Telangiectasia Mutated Proteins drug effects, Carbon-Nitrogen Lyases antagonists & inhibitors, Enzyme Inhibitors pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL., Competing Interests: The authors declare no conflicts of interest
- Published
- 2016
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