Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Abstract

Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.

Exploration of the molecular mechanisms, shared gene signatures, and MicroRNAs between systemic lupus erythematosus and diffuse large B cell lymphoma by bioinformatics analysis

“…28 Psmb4 promotes tumor proliferation through the NF-κB pathway. 30,31 Bortezomib, a proteasome inhibitor, was the first approved inhibitor targeting NF-κB for treatment of SLE and DLBCL. [32][33][34] Our study found that hsa-mir-155-5p acted as the core shared miRNA of the two diseases.…”

“…28 Psmb4 promotes tumor proliferation through the NF-κB pathway. 30,31 Bortezomib, a proteasome inhibitor, was the first approved inhibitor targeting NF-κB for treatment of SLE and DLBCL. 32–34…”

Site-Specific Proteasome Inhibitors

“…Given the importance of Pro for β1 specificity, would degradation of Pro-rich proteins be sensitive to β1 inhibitors? A recent study demonstrating that sub-toxic, site-specific doses of NC-005, NC-001, and LU-102 exert subtle but distinct effects on the phosphorylation patterns of key regulatory proteins in myeloma cells [ 128 ] suggest the untapped biological potential of these reagents.…”