ROLE OF OXLDL IN METABOLIC SYNDROME-ASSOCIATED RESISTANCE OF MYELOMA TO PROTEASOME INHIBITORS

Proteasome inhibitor (PI) therapy has been crucial to the improved survival of patients withmultiple myeloma (MM). Unfortunately, primary and acquired resistance to PIs contributes todisease progression and death. Obesity and/or insulin resistance are risk factors for MM mortality.Dysregulated inflammatory and metabolic factors in the metabolic syndrome or its associatedcomponents (obesity/insulin resistance/dyslipidemia) decrease the efficacy of chemotherapeuticsfor various tumor types, and likely contribute to chemoresistance and disease progression in MMpatients. Our preliminary studies suggest that oxidized low-density lipoprotein (OxLDL), anoxidatively modified lipoprotein that is elevated in the metabolic syndrome, may be a potentcontributor to MM resistance to PIs. Since the MM microenvironment contains numerousgranulocytic cells and monocytes that express myeloperoxidase (MPO), a potent mediator of LDLoxidation, MM cells are likely exposed to high levels of OxLDL in disorders associated withhypercholesterolemia/dyslipidemia. This notion is supported by our detection of OxLDL in closeproximity to MM cells and MPO-expressing cells in bone marrow samples from newly diagnosedMM patients. We have observed in cell culture experiments that OxLDL potently suppresses MMcell killing by bortezomib (VELCADE), a frontline chemotherapeutic used to treat MM. We havepreliminary evidence that OxLDL, protects MM cells from PI-induced cytotoxicity by restoringproteasome activity. The proposed project aims to reveal key pathways involved in mediating theprotective effect of OxLDL against PI-induced MM cell killing, and evaluate the potential ofsuppressing elevated OxLDL levels associated with hypercholesterolemia/dyslipidemia toenhance MM responsiveness to therapeutic PIs.