Skip to Main content Skip to Navigation
Journal articles

PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance

Abstract : The aim of this study was to assess the efficiency of p53 reactivation and induction of massive apoptosis (PRIMA-1(Met)) in inducing myeloma cell death, using 27 human myeloma cell lines (HMCLs) and 23 primary samples. Measuring the lethal dose (LD50) of HMCLs revealed that HMCLs displayed heterogeneous sensitivity, with an LD50 ranging from 4 μM to more than 200 μM. The sensitivity of HMCLs did not correlate with myeloma genomic heterogeneity or TP53 status, and PRIMA-1(Met) did not induce or increase expression of the p53 target genes CDKN1A or TNFRSF10B/DR5. However, PRIMA-1(Met) increased expression of NOXA in a p53-independent manner, and NOXA silencing decreased PRIMA1(Met)-induced cell death. PRIMA-1(Met) depleted glutathione (GSH) content and induced reactive oxygen species production. The expression of GSH synthetase correlated with PRIMA-1(Met) LD50 values, and we showed that a GSH decrease mediated by GSH synthetase silencing or by and L-buthionine sulphoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, increased PRIMA-1(Met)-induced cell death and overcame PRIMA-1(Met) resistance. PRIMA-1(Met) (10 μM) induced cell death in 65% of primary cells independent of the presence of del17p; did not increase DR5 expression, arguing against an activation of p53 pathway; and synergized with L-buthionine sulphoximine in all samples. Finally, we showed in mouse TP53(neg) JJN3-xenograft model that PRIMA-1(Met) inhibited myeloma growth and synergized with L-buthionine sulphoximine in vivo.
Document type :
Journal articles
Complete list of metadata

https://www.hal.inserm.fr/inserm-03290437
Contributor : Pellat-Deceunynck Pellat-Deceunynck Connect in order to contact the contributor
Submitted on : Monday, July 19, 2021 - 1:00:11 PM
Last modification on : Friday, July 30, 2021 - 3:16:57 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Benoît Tessoulin, Géraldine Descamps, Philippe Moreau, Sophie Maïga, Laurence Lodé, et al.. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood, American Society of Hematology, 2014, 124 (10), pp.1626 - 1636. ⟨10.1182/blood-2014-01-548800⟩. ⟨inserm-03290437⟩

Share

Metrics

Record views

19