Pyrroline-5-Carboxylate Reductase 1: a novel target for sensitizing multiple myeloma cells to bortezomib by inhibition of PRAS40-mediated protein synthesis.
Hypoxia
Multiple myeloma
PYCR1
Proline
Protein synthesis
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
01 Feb 2022
01 Feb 2022
Historique:
received:
30
09
2021
accepted:
07
01
2022
entrez:
2
2
2022
pubmed:
3
2
2022
medline:
24
3
2022
Statut:
epublish
Résumé
Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1 and PYCR2) are two mitochondrial enzymes that facilitate the last step in the glutamine-to-proline conversion. Overexpression of PYCR1 is involved in progression of several cancers, however, its' role in hematological cancers is unknown. In this study, we investigated whether PYCR affects MM viability, proliferation and response to bortezomib. Correlation of PYCR1/2 with overall survival was investigated in the MMRF CoMMpass trial (653 patients). OPM-2 and RPMI-8226 MM cell lines were used to perform in vitro experiments. RPMI-8226 cells were supplemented with We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of This study identifies PYCR1 as a novel target in bortezomib-based combination therapies for MM.
Sections du résumé
BACKGROUND
BACKGROUND
Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1 and PYCR2) are two mitochondrial enzymes that facilitate the last step in the glutamine-to-proline conversion. Overexpression of PYCR1 is involved in progression of several cancers, however, its' role in hematological cancers is unknown. In this study, we investigated whether PYCR affects MM viability, proliferation and response to bortezomib.
METHODS
METHODS
Correlation of PYCR1/2 with overall survival was investigated in the MMRF CoMMpass trial (653 patients). OPM-2 and RPMI-8226 MM cell lines were used to perform in vitro experiments. RPMI-8226 cells were supplemented with
RESULTS
RESULTS
We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of
CONCLUSIONS
CONCLUSIONS
This study identifies PYCR1 as a novel target in bortezomib-based combination therapies for MM.
Identifiants
pubmed: 35105345
doi: 10.1186/s13046-022-02250-3
pii: 10.1186/s13046-022-02250-3
pmc: PMC8805317
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Synthesis Inhibitors
0
Bortezomib
69G8BD63PP
Pyrroline Carboxylate Reductases
EC 1.5.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
45Subventions
Organisme : Fonds Wetenschappelijk Onderzoek
ID : FWOAL806
Organisme : Vrije Universiteit Brussel
ID : SRP48
Informations de copyright
© 2022. The Author(s).
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