The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma

• DOI: 10.1182/bloodadvances.2020002578
• Publication Date: 2021-04-06T16:28:44Z
• Authors: Brittany C. Lipchick; Adam Utley; Zhannan Han; Sudha Moparthy; Dong Hyun Yun; Anna Bianchi-Smir...; David W. Wolff; Emily Fink; Liang Liu; Cristina M. Furdui; Jingyun Lee; Kelvin P. Lee; Mikhail A. Nikiforov
• Keywords: 0303 health sciences; 571; Fatty Acid Elongases; 610; Neoplasm drug resistance; Bortezomib; Mice; 03 medical and health sciences; Multiple myeloma; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; Humans; Multiple Myeloma; Fatty acid elongases

AbstractResistance to the proteasome inhibitor bortezomib (BTZ) represents a major obstacle in the treatment of multiple myeloma (MM). The contribution of lipid metabolism in the resistance of MM cells to BTZ is mostly unknown. Here we report that levels of fatty acid elongase 6 (ELOVL6) were lower in MM cells from BTZ-nonresponsive vs BTZ-responsive patients and in cultured MM cells selected for BTZ resistance compared with parental counterparts. Accordingly, depletion of ELOVL6 in parental MM cells suppressed BTZ-induced endoplasmic reticulum (ER) stress and cytotoxicity, whereas restoration of ELOVL6 levels in BTZ-resistant MM cells sensitized them to BTZ in tissue culture settings and, as xenografts, in a plasmacytoma mouse model. Furthermore, for the first time, we identified changes in the BTZ-induced lipidome between parental and BTZ-resistant MM cell lines underlying a functional difference in their response to BTZ. We demonstrated that restoration of ELOVL6 levels in BTZ-resistant MM cells resensitized them to BTZ largely via upregulation of ELOVL6-dependent ceramide species, which was a prerequisite for BTZ-induced ER stress and cell death in these cells. Our data characterize ELOVL6 as a major clinically relevant regulator of MM cell resistance to BTZ, which can emerge from the impaired ability of these cells to alter ceramide composition in response to BTZ.