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PreprintCited by 27Genomics, phytochemicals, and oxidative stressNF-κB Signaling PathwaysLung Cancer Treatments and Mutations

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Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells

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Deen, Ashik Jawahar, Adinolfi, Simone, Härkönen, Jouni, Patinen, Tommi, Liu, Xiaonan, Laitinen, Tuomo, Takabe, Piia, Kainulainen, Kirsi, Pasonen-Seppänen, Sanna, Gawriyski, Lisa M, Arasu, Uma Thanigai, Selvarajan, Ilakya, Mäkinen, Petri, Laitinen, Hanna, Kansanen, Emilia, Kaikkonen, Minna U, Poso, Antti, Varjosalo, Markku, Levonen, Anna-Liisa·2023·Redox Biology
DOI 10.1101/2023.10.10.561664PMC PMC10808971

Preprint — published as 10.1016/j.redox.2024.103031 · Paper page

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Abstract

The Kelch-like ECH-associated protein 1 (KEAP1) – Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα) – Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and the mutants was employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis.

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Metadata

Authors
Deen, A. J., Adinolfi, S., Härkönen, J., Patinen, T., Liu, X., Laitinen, T., Takabe, P., Kainulainen, K., Pasonen-Seppänen, S., Gawriyski, L. M., Arasu, U. T., Selvarajan, I., Mäkinen, P., Laitinen, H., Kansanen, E., Kaikkonen, M. U., Poso, A., Varjosalo, M., & Levonen, A.-L.
Affiliations
  • University of Eastern Finland (FI)
  • University of Helsinki (FI)
Corresponding author
Levonen, Anna-Liisa
ORCID
Venue
Redox Biology
Publisher
openRxiv
Published
2023-10-12
Volume
69
Pages
103031-103031
ISSN
2213-2317 (ISSN-L)
DOI
10.1101/2023.10.10.561664
PMC
PMC10808971
OpenAlex
W4390581647
Cited by
27
References
1
Citations by year
2026: 7 · 2025: 12 · 2024: 8
FWCI
3.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Redox Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
KEAP1 mutation, TRAF2, NF-κB signaling, apoptosis resistance, non-small cell lung cancer, lung adenocarcinoma, Nrf2/Keap1 pathway, TNF signaling, XIAP, protein-protein interaction, c-Myc, mTORC1, oxidative stress response
MeSH terms
Kelch-Like ECH-Associated Protein 1, Adenocarcinoma of Lung, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, NF-kappa B, Apoptosis, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, TNF Receptor-Associated Factor 2, NF-E2-Related Factor 2

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