NEMO- and RelA-dependent NF-κB signaling promotes small cell lung cancer.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
12
07
2022
accepted:
06
01
2023
revised:
28
12
2022
medline:
5
4
2023
pubmed:
19
1
2023
entrez:
18
1
2023
Statut:
ppublish
Résumé
Small cell lung cancer (SCLC) is an aggressive type of lung cancer driven by combined loss of the tumor suppressors RB1 and TP53. SCLC is highly metastatic and despite good initial response to chemotherapy patients usually relapse, resulting in poor survival. Therefore, better understanding of the mechanisms driving SCLC pathogenesis is required to identify new therapeutic targets. Here we identified a critical role of the IKK/NF-κB signaling pathway in SCLC development. Using a relevant mouse model of SCLC, we found that ablation of NEMO/IKKγ, the regulatory subunit of the IKK complex that is essential for activation of canonical NF-κB signaling, strongly delayed the onset and growth of SCLC resulting in considerably prolonged survival. In addition, ablation of the main NF-κB family member p65/RelA also delayed the onset and growth of SCLC and prolonged survival, albeit to a lesser extent than NEMO. Interestingly, constitutive activation of IKK/NF-κB signaling within the tumor cells did not exacerbate the pathogenesis of SCLC, suggesting that endogenous NF-κB levels are sufficient to fully support tumor development. Moreover, TNFR1 deficiency did not affect the development of SCLC, showing that TNF signaling does not play an important role in this tumor type. Taken together, our results revealed that IKK/NF-κB signaling plays an important role in promoting SCLC, identifying the IKK/NF-κB pathway as a promising therapeutic target.
Identifiants
pubmed: 36653597
doi: 10.1038/s41418-023-01112-5
pii: 10.1038/s41418-023-01112-5
pmc: PMC10070460
doi:
Substances chimiques
I-kappa B Kinase
EC 2.7.11.10
Intracellular Signaling Peptides and Proteins
0
NEMO protein, mouse
0
NF-kappa B
0
Rela protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
938-951Informations de copyright
© 2023. The Author(s).
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