Chemoresistance in multiple myeloma: oxidized LDL suppresses the anti‐myeloma effects of boronic‐based proteasome inhibitors

Abstract

Multiple myeloma (MM) is a malignancy of plasma cells that accumulate in the bone marrow. While treatment advances, particularly proteasome inhibitors (PIs) and immunomodulatory drugs, have improved survival, MM remains incurable. Obesity and insulin resistance are risk factors for MM mortality. Oxidized‐low density lipoprotein (OxLDL), a key atherogenic factor that is frequently elevated in these metabolic abnormalities, has emerged as a risk factor for the development and progression of solid cancers; its role in MM is unexplored. We evaluated the influence of OxLDL on MM cell killing by therapeutic proteasome inhibitors (PIs). OxLDL, at concentrations within the range reported for patients with obesity/insulin resistance/dyslipidemia, potently suppressed MM cell killing by the reversible boronic‐based PIs bortezomib (BTZ) and ixazomib but not the irreversible epoxyketone‐based PI carfilzomib. Native low‐density lipoprotein (nLDL) did not affect the anti‐MM effects of these PIs, which suggests that the oxidative modification of lipids or apolipoprotein in OxLDL are the mediators of cytoprotection. OxLDL suppressed BTZ‐induced inhibition of proteasome activity, accumulation of ubiquinated proteins, and induction of pro‐apoptotic unfolded protein response signaling. The cytoprotective effects of OxLDL were abrogated when lipid hydroperoxides (LOOHs) associated with the lipoprotein were specifically reduced by pretreatment with the glutathione‐dependent selenoperoxidase mimetic ebselen. Because boronic‐based PIs are vulnerable to oxidative degradation, we explored the possibility that OxLDL was inactivating bortezomib extracellularly. When MM cells were simultaneously treated with catalase and/or superoxide dismutase, OxLDL, and BTZ, the ROS scavengers did not affect OxLDL's ability to suppress bortezomib‐induced inhibition of proteasome activity. OxLDL rapidly and potently induced signaling through multiple pathways associated with cell survival and/or chemoresistance including AKT, PKC, BCL‐2 and NRF2. Finally, immunohistochemical analysis of bone marrow biopsy samples from newly diagnosed MM patients demonstrated the presence of OxLDL in macrophages scattered among MM cells. Thus, MM cells likely interact with OxLDL in the MM microenvironment and may be exposed to high levels of the lipoprotein in MM patients with dyslipidemia. Our data suggest that OxLDL counteracts the anti‐MM effects of PIs through LOOHs that trigger intracellular signaling that prevents/restores proteasome activity, which is significant since LDL is a major carrier of LOOHs in the plasma. Thus, OxLDL may be a potent mediator of chemoresistance to therapeutic PIs in obese/insulin resistant/dyslipidemic MM patients. Our findings also raise the potential benefit of LDL cholesterol‐lowering therapy, or targeting prosurvival signaling pathways used by OxLDL, to increase the efficacy of therapeutic PIs and improve the survival of obese/insulin resistant MM patients.Support or Funding InformationThis work was supported by NIH grants RO1 AT006885 (RA) and R21CA227414 (EAM), a Max and Minnie Tomerlin Voelcker Fund Young Investigator Award (EAM).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.