The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells.
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.
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.
Andrea
A
Tomasella
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.
Raffaella
R
Picco
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.
Sonia
S
Ciotti
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.
Andrea
A
Sgorbissa
Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Elisa
E
Bianchi
Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Rossella
R
Manfredini
Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy.
Fabio
F
Benedetti
Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Valentina
V
Trimarco
Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Federica
F
Frezzato
Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Livio
L
Trentin
Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
Gianpietro
G
Semenzato
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Domenico
D
Delia
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.|Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Claudio
C
Brancolini
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000187:drug effects* / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology; D019759:Carbon-Nitrogen Lyases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000069286:Bortezomib; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D046988:Proteasome Endopeptidase Complex; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase
CLL; apoptosis; deubuquitylases; proteasome; proteotoxic stress