Targeting lipid metabolism in multiple myeloma cells: Rational development of a synergistic strategy with proteasome inhibitors

Abstract

Background and Purpose Aberrant lipid metabolism is recognized as a key feature of cancer cells. Our initial research on MS‐based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in multiple myeloma cells after proteasome inhibition. This finding prompted us to hypothesize that multiple myeloma cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism‐modulating agents would synergize with proteasome inhibitors. Experimental Approach Lipid accumulation in multiple myeloma cells was measured by MS. Synergism between lipid regulators and proteasome inhibitors was assessed by cell viability and apoptosis. A novel stable derivative of fenofibrate (FCE) was synthesized and used to treat multiple myeloma cells in vitro and in vivo along with the proteasome inhibitor ixazomib. ChIP‐seq, western blotting and RT‐qPCR were performed to explore the potential mechanism(s) underlying the increase in lipid levels in multiple myeloma cells after proteasome inhibition. Key Results Accumulation of lipids in multiple myeloma cells was induced by proteasome inhibition. Lipid‐lowering drugs and MG‐132 exerted a synergistic effect to kill multiple myeloma cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in multiple myeloma cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4. Conclusions and Implications Our results provide a proof of principle and support for the further clinical evaluation of the combination of lipid‐modulating drugs with proteasome inhibitors in the treatment of multiple myeloma.

Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma

“…ATF4 becomes activated in response to an integrated stress response [ 69 ] or pro-growth signaling [ 91 ]. While basal expression of ATF4 may attenuate PI-induced apoptosis in MM cells [ 92 ], ATF4 induction promotes PI resistance by facilitating lipogenesis [ 93 ]. In supporting a role in regulating chromatin accessibility, ATF4 promotes histone acetylation [ 94 ], reduces repressive H3K9 methylation in target genes [ 95 ], and is implicated as a pioneer factor by recognizing methylated DNA together with CEBPβ [ 90 ].…”

Metabolic Disorders in Multiple Myeloma

“…On the other hand, there is accumulating recent evidence to suggest that statin use may reduce both the risk of MM development and mortality [ 139 , 140 ]. Interestingly, the combination of lipid-lowering agents with proteasome inhibitors has shown to have a synergistic effect against myeloma cells [ 141 ].…”

“…Interestingly, anti-mitochondrial agents have shown to restore the sensitivity of myeloma cells to proteasome inhibitors [ 39 ]. The combination of metabolic regulators with proteasome inhibitors may induce synthetic lethality, prevent the activation of resistance mechanisms and increase efficacy [ 141 , 149 ]. Recently, preclinical studies have shown that adaptive natural killer cells have decreased CD38 expression and enhanced metabolic fitness by resisting oxidative stress, which may lead to improved anti-myeloma activity in the relapsed disease setting [ 150 , 151 ].…”

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

“…Aberrant lipid metabolism is recognized as a key feature of MM [ 68 ]. A previous study has reported a significant accumulation of lipids in MM cells after proteasome inhibition [ 69 ]. Our metabolic analysis, performed in a lenalidomide-resistant cell line, showed a similar trend after lenalidomide treatment in MM cell lines.…”