Abstract 4808
Background
NORE1A/RASSF5 is a tumor suppressor that is commonly inactivated in a variety of cancers. NORE1A is frequently down-regulated during tumor development and its inactivation often correlates with up-regulation of Ras activity. Although NORE1A was reported to be activated by NF-kB, its role in NF-kB signaling and the underlying mechanism have not been addressed. In this study, we explored the role for NORE1A in the regulation and function of the TNF-NF-kB pathway.
Methods
NORE1A effect on TNF regulation of inflammation, growth, and apoptosis was examined by flow cytometry, migration and invasion, and apoptosis assays. NORE1A regulation of TNF-NF-kB signaling was analyzed by quantitative RT-PCR, immunoblot, immunoprecipitation, and promoter luciferase assay.
Results
Upon exposure to TNF-a, NORE1A is induced by NF-kB signaling at the level of transcription while its activation suppresses TNF activation of NF-kB, indicating that NORE1A functions as a feedback terminator of TNF-NF-kB signaling. As predicted, NORE1A blocks TNF activation of pro-inflammatory gene transcription, epithelial-to-mesenchymal transition (EMT), invasion and migration. Mechanistically, NORE1A binds directly to TNF receptor I (TNFR1) and ubiquitin E3 ligase ITCH to promote ITCH-mediated K48-linked ubiquitination of TNFR1 and subsequent lysosomal degradation. Additionally, we identified that the PPXY motif of NORE1A interacts directly with ITCH using a series of deletion mutants. This interaction protects BAX from ITCH-mediated ubiquitination and thus activates its apoptotic function. NORE1A interaction with ITCH plays a crucial role for both TNFR1 degradation and BAX stabilization and activation.
Conclusions
In this study, we demonstrate first that NORE1A is a feedback terminator of TNF-NF-kB signaling, which directly antagonizes TNFR1 by facilitating the ITCH-TNFR1 interaction. Our study also shows that NORE1A binding to ITCH releases ITCH from BAX and activates BAX-mediated apoptosis. These data illuminate the mechanistic consequence of NORE1A inactivation in tumorigenesis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Sung-gil, Chi.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1851 - Nivolumab-induced and radiation recall pneumonitis in patients with non-small cell lung cancer: a multicenter real world analysis of 669 patients
Presenter: Nobuaki Mamesaya
Session: Poster Display session 1
Resources:
Abstract
851 - Retrospective analysis of immunotherapy prognostic scores in advanced NSCLC at Nottingham University Hospitals (UK)
Presenter: Cristina Lopez Escola
Session: Poster Display session 1
Resources:
Abstract
3639 - Applicability of lung immune prognostic index (LIPI) to predict efficacy of first-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC)
Presenter: Xabier Mielgo Rubio
Session: Poster Display session 1
Resources:
Abstract
2950 - Delayed Onset Immune Related Adverse Effects (IRAEs) of Pembrolizumab in Non-Small Cell Lung Cancer
Presenter: Haixi Yan
Session: Poster Display session 1
Resources:
Abstract
3659 - Clinical implication of multiplex IHC and serologic biomarkers on Hyperprogression in NSCLC patients receiving Immune checkpoint blockers in real world.
Presenter: Joori Kim
Session: Poster Display session 1
Resources:
Abstract
4882 - Local ablative treatment and treatment beyond progression for oligo-progression in stage IV non-small cell lung cancer after tumor response to anti-PD1 treatment
Presenter: Florian Guisier
Session: Poster Display session 1
Resources:
Abstract
1358 - Atezolizumab in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs)
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract
2170 - Prognostic Impact of Metastatic Sites for Pembrolizumab Efficacy as First-line therapy in Patients with PD-L1 tumor proportion score (TPS) ≥ 50% Advanced Non–Small Cell Lung Cancer: A Retrospective Multicenter Study
Presenter: Hayato Kawachi
Session: Poster Display session 1
Resources:
Abstract
3051 - Impact of visceral fat area as independent predictive factor in patients with advanced non-small cell lung cancer treated with nivolumab
Presenter: Yuki Sato
Session: Poster Display session 1
Resources:
Abstract
3409 - Effect and safety of immune checkpoint inhibitors for brain metastases from non-small cell lung cancer
Presenter: Toshihiko Iuchi
Session: Poster Display session 1
Resources:
Abstract