SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma.
Malignant pleural mesothelioma
Pevonedistat
SKP/Cullin/F-box complex
endoplasmic reticulum stress
immunogenic cell death
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:
23 Feb 2022
23 Feb 2022
Historique:
received:
12
08
2021
accepted:
10
02
2022
entrez:
24
2
2022
pubmed:
25
2
2022
medline:
31
3
2022
Statut:
epublish
Résumé
The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results. Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat. In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8 We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.
Sections du résumé
BACKGROUND
BACKGROUND
The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results.
METHODS
METHODS
Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat.
RESULTS
RESULTS
In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8
CONCLUSIONS
CONCLUSIONS
We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.
Identifiants
pubmed: 35197103
doi: 10.1186/s13046-022-02284-7
pii: 10.1186/s13046-022-02284-7
pmc: PMC8864928
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
S-Phase Kinase-Associated Proteins
0
Pemetrexed
04Q9AIZ7NO
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
75Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG23760
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG21408
Organisme : ASO Alessandria
ID : MESOLINE
Organisme : Fondazione Cassa di Risparmio di Torino
ID : ID 2018.0568
Organisme : Fondazione Cassa di Risparmio di Torino
ID : ID 2020.1648
Organisme : ERA-Net Transcan-2-JTC 2017
ID : TOPMESO
Informations de copyright
© 2022. The Author(s).
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