Oxidatively modified low‐density lipoproteins are potential mediators of proteasome inhibitor resistance in multiple myeloma. Issue 12 (8th March 2021) - Polusani, Srikanth R.
Abstract: Proteasome inhibitor (PI) therapy has improved the survival of multiple myeloma (MM) patients. However, inevitably, primary or acquired resistance to PIs leads to disease progression; resistance mechanisms are unclear. Obesity is a risk factor for MM mortality. Oxidized LDL (OxLDL), a central mediator of atherosclerosis that is elevated in metabolic syndrome (co‐occurrence of obesity, insulin resistance, dyslipidemia and hypertension), has been linked to an increased risk of solid cancers and shown to stimulate pro‐oncogenic/survival signaling. We hypothesized that OxLDL is a mediator of chemoresistance and evaluated its effects on MM cell killing by PIs. OxLDL potently suppressed the ability of the boronic acid‐based PIs bortezomib (BTZ) and ixazomib, but not the epoxyketone‐based PI carfilzomib, to kill human MM cell lines and primary cells. OxLDL suppressed BTZ‐induced inhibition of proteasome activity and induction of pro‐apoptotic signaling. These cytoprotective effects were abrogated when lipid hydroperoxides (LOOHs) associated with OxLDL were enzymatically reduced. We also demonstrated the presence of OxLDL in the MM bone marrow microenvironment as well as numerous granulocytes and monocytes capable of cell‐mediated LDL oxidation through myeloperoxidase. Our findings suggest that OxLDL may be a potent mediator of boronic acid‐based PI resistance, particularly for MM patients with metabolic syndrome, given their elevated systemic levels of OxLDL. LDL cholesterol‐lowering therapy to reduce circulating OxLDL, and pharmacologic targeting of LOOH levels or resistance pathways induced by the modified lipoprotein, could deepen the response to these important agents and offer clinical benefit to MM patients with metabolic syndrome. Abstract : What's new? Circulating levels of oxidized LDL are elevated in obesity. OxLDL stimulates pro‐survival signaling in different cell types and may play a role in the increased multiple myeloma (MM) mortality associated with obesity. Here, OxLDL, via associated lipid hydroperoxides (LOOHs), potently suppressed the inhibition of proteasome activity and MM cell killing by bortezomib and ixazomib. The findings suggest that OxLDL may be a mediator of resistance to these boronic acid‐based proteasome inhibitors. Reduction of circulating OxLDL by LDL cholesterol‐lowering therapy, and pharmacological targeting of LOOH levels or OxLDL‐induced resistance pathways, could potentially be used to deepen the response to proteasome inhibitors.