Targeting lipid metabolism in multiple myeloma cells: Rational development of a synergistic strategy with proteasome inhibitors
| Autor: | Xiaofang Gao, Zuofeng Liu, Yu Wang, Minhui Li, Ping Li, Pengfan Qie, Dong Renhan, Xu Gaojie, Lijuan Su, Peng Jian, Bin Guang, Sisi Yu, Siyuan Liu, Huang Sheng, Jin Liu, Siqi Yu, Hu Wen, Tai Yang |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Proteasome Endopeptidase Complex Chemistry Antineoplastic Agents Apoptosis Lipid metabolism Lipid Metabolism medicine.disease Ixazomib Bortezomib chemistry.chemical_compound Proteasome Cell culture Cell Line Tumor Cancer cell Cancer research Proteasome inhibitor medicine Humans Viability assay Multiple Myeloma Proteasome Inhibitors Multiple myeloma medicine.drug |
| Zdroj: | British Journal of Pharmacology. 178:4741-4757 |
| ISSN: | 1476-5381 0007-1188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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