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The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma

Publication ,  Journal Article
Lipchick, BC; Utley, A; Han, Z; Moparthy, S; Yun, DH; Bianchi-Smiraglia, A; Wolff, DW; Fink, E; Liu, L; Furdui, CM; Lee, J; Lee, KP; Nikiforov, MA
Published in: Blood Advances
April 13, 2021

Resistance 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.

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Published In

Blood Advances

DOI

EISSN

2473-9537

ISSN

2473-9529

Publication Date

April 13, 2021

Volume

5

Issue

7

Start / End Page

1933 / 1946

Publisher

American Society of Hematology

Related Subject Headings

  • 3201 Cardiovascular medicine and haematology
 

Citation

APA
Chicago
ICMJE
MLA
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Lipchick, B. C., Utley, A., Han, Z., Moparthy, S., Yun, D. H., Bianchi-Smiraglia, A., … Nikiforov, M. A. (2021). The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma. Blood Advances, 5(7), 1933–1946. https://doi.org/10.1182/bloodadvances.2020002578
Lipchick, Brittany C., Adam Utley, Zhannan Han, Sudha Moparthy, Dong Hyun Yun, Anna Bianchi-Smiraglia, David W. Wolff, et al. “The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma.” Blood Advances 5, no. 7 (April 13, 2021): 1933–46. https://doi.org/10.1182/bloodadvances.2020002578.
Lipchick BC, Utley A, Han Z, Moparthy S, Yun DH, Bianchi-Smiraglia A, et al. The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma. Blood Advances. 2021 Apr 13;5(7):1933–46.
Lipchick, Brittany C., et al. “The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma.” Blood Advances, vol. 5, no. 7, American Society of Hematology, Apr. 2021, pp. 1933–46. Crossref, doi:10.1182/bloodadvances.2020002578.
Lipchick BC, Utley A, Han Z, Moparthy S, Yun DH, Bianchi-Smiraglia A, Wolff DW, Fink E, Liu L, Furdui CM, Lee J, Lee KP, Nikiforov MA. The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma. Blood Advances. American Society of Hematology; 2021 Apr 13;5(7):1933–1946.

Published In

Blood Advances

DOI

EISSN

2473-9537

ISSN

2473-9529

Publication Date

April 13, 2021

Volume

5

Issue

7

Start / End Page

1933 / 1946

Publisher

American Society of Hematology

Related Subject Headings

  • 3201 Cardiovascular medicine and haematology