The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
13 04 2021
13 04 2021
Historique:
received:
04
06
2020
accepted:
10
02
2021
entrez:
6
4
2021
pubmed:
7
4
2021
medline:
1
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33821992
pii: S2473-9529(21)00239-1
doi: 10.1182/bloodadvances.2020002578
pmc: PMC8045499
doi:
Substances chimiques
Bortezomib
69G8BD63PP
Fatty Acid Elongases
EC 2.3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1933-1946Subventions
Organisme : NCI NIH HHS
ID : R01 CA224434
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA012197
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193981
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190533
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA247819
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
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