Abstract
Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor-kappaB (NF-κB) p65, pp65, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.
Highlights
The proteasome inhibitor bortezomib is effective at treating multiple myeloma (MM) because the efficacy of bortezomibbased chemotherapy regimens is as high as 80%–90% (Rajkumar, 2016), drug resistance limits its repeated use, the mechanisms are not fully understood (Malard et al, 2017)
The bortezomib-resistant cell line NCI-H929.BR was established, and changes in p53-induced RING-H2 (Pirh2) expression were identified to evaluate the role of the E3 ubiquitin ligase Pirh2 in bortezomib resistance in MM
E3 ligases are of interest as drug targets because of their ability to regulate protein stability and functions (Liu et al, 2014), especially in oncogenesis (Jung et al, 2012, Hsieh et al, 2013, Severe et al, 2013, Sharma and Nag, 2014, Zhang et al, 2014, Hao and Huang, 2015, Yin et al, 2015), cancer progression (Lou and Wang, 2014, Sun and Denko, 2014, Goka and Lippman, 2015), metastasis (Wang et al, 2012), disease prognosis (Bielskiene et al, 2015, Hou and Deng, 2015) and chemotherapy resistance (Nelson et al, 2016, Petzold et al, 2016)
Summary
The proteasome inhibitor bortezomib is effective at treating multiple myeloma (MM) because the efficacy of bortezomibbased chemotherapy regimens is as high as 80%–90% (Rajkumar, 2016), drug resistance limits its repeated use, the mechanisms are not fully understood (Malard et al, 2017). The molecular mechanisms of bortezomib resistance need to be urgently explored to enhance the use of existing treatments and to define more effective single or combination therapies. The current established molecular mechanisms underlying resistance to proteasome inhibitors involve constitutive and immunoproteasomes, mutated proteasome subunits, unfolded protein response (UPR) mediators, multidrug efflux transporters, aggresomes, autophagosomes, pro-survival signaling pathway mediators, or bone marrow microenvironmental components (Niewerth et al, 2015). E3 ubiquitin ligases determine the specificity of protein degradation, and these ligases have been shown to be closely related to cancer occurrence, development, transfer, and drug resistance
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