The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

Andrea Tomasella, Raffaella Picco, Sonia Ciotti, Andrea Sgorbissa, Elisa Bianchi, Rossella Manfredini, Fabio Benedetti, Valentina Trimarco, Federica Frezzato, Livio Trentin, Gianpietro Semenzato, Domenico Delia, Claudio Brancolini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)45429-45443
Number of pages15
JournalOncotarget
Volume7
Issue number29
DOIs
Publication statusPublished - 2016

Keywords

  • Apoptosis
  • CLL
  • Deubuquitylases
  • Proteasome
  • Proteotoxic stress

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells'. Together they form a unique fingerprint.

Cite this