Expression of E3 Ubiquitin Ligases in Multiple Myeloma Patients after Treatment with the Proteasome Inhibitor Bortezomib

Abstract

Aim: Clinical success of the proteasome inhibitor bortezomib for multiple myeloma (MM) treatment highlights the potential of therapeutically targeting the ubiquitin (Ub) + proteasome system. However, bortezomib treatment invariably leads to therapeutic resistance through mechanisms that remain elusive and that limit long-term clinical efficacy. We hypothesized that individual E3 Ub ligases were differentially expressed in MM patients that did or did not respond to bortezomib. E3 ligases bind intracellular protein substrates leading to their subsequent ubiquitination that then triggers proteasomal degradation of the substrate. The aim of the present study was to analyze the gene expression profiles (GEPs) from MM patients and identify E3 Ub ligases that correlated with clinical response to bortezomib. Methods: MM tumor cells were collected by bone marrow biopsy from newly diagnosed patients, and RNA isolated and GEPs were correlated with individual patient response to bortezomib. Results: Expression of the E3 Ub ligase Skp1-Cullin-1-F-box (SCF)-Skp2 was significantly increased in MM patients that did not respond to bortezomib. However, SCF-Skp2 expression was not increased in GEPs from patients that did not respond to other anti-myeloma agents. Conclusion: Drugs that target the E3 Ub ligase SCF-Skp2 may overcome bortezomib resistance and display refined specificity with reduced adverse toxicities.