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Cited by 189NF-κB Signaling PathwaysProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

Requirement of the NF-κB Subunit p65/RelA for K-Ras–Induced Lung Tumorigenesis

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Bassères, Daniela S., Ebbs, Aaron, Levantini, Elena, Baldwin, Albert S.·2010·Cancer Research
DOI 10.1158/0008-5472.can-09-4290PMC PMC2862109
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Abstract

K-Ras-induced lung cancer is a very common disease, for which there are currently no effective therapies. Because therapy directly targeting the activity of oncogenic Ras has been unsuccessful, a different approach for novel therapy design is to identify critical Ras downstream oncogenic targets. Given that oncogenic Ras proteins activate the transcription factor NF-kappaB, and the importance of NF-kappaB in oncogenesis, we hypothesized that NF-kappaB would be an important K-Ras target in lung cancer. To address this hypothesis, we generated a NF-kappaB-EGFP reporter mouse model of K-Ras-induced lung cancer and determined that K-Ras activates NF-kappaB in lung tumors in situ. Furthermore, a mouse model was generated where activation of oncogenic K-Ras in lung cells was coupled with inactivation of the NF-kappaB subunit p65/RelA. In this model, deletion of p65/RelA reduces the number of K-Ras-induced lung tumors both in the presence and in the absence of the tumor suppressor p53. Lung tumors with loss of p65/RelA have higher numbers of apoptotic cells, reduced spread, and lower grade. Using lung cell lines expressing oncogenic K-Ras, we show that NF-kappaB is activated in these cells in a K-Ras-dependent manner and that NF-kappaB activation by K-Ras requires inhibitor of kappaB kinase beta (IKKbeta) kinase activity. Taken together, these results show the importance of the NF-kappaB subunit p65/RelA in K-Ras-induced lung transformation and identify IKKbeta as a potential therapeutic target for K-Ras-induced lung cancer.

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  • Mutated K-RAS activates NF-κB in a mouse model of lung cancer.

    “Mutated K-RAS activates NF-κB in a mouse model of lung cancer (315), and the K-RAS-induced activation of NF-κB is required for pancreatic cancer development (316), which depends on IL-6 trans-signaling-mediated STAT3 activation (317).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [315]

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Cited by

Sorted by citations

Authors
Bassères, D. S., Ebbs, A., Levantini, E., & Baldwin, A. S.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Baldwin, Albert S.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2010-04-28
Volume
70
Issue
9
Pages
3537-3546
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-09-4290
PMC
PMC2862109
OpenAlex
W1985538305
Cited by
189
References
5
Citations by year
2026: 3 · 2025: 9 · 2024: 6 · 2023: 10 · 2022: 7 · 2021: 13 · 2020: 14 · 2019: 11 · 2018: 13 · 2017: 8 · 2016: 13 · 2015: 9 · 2014: 14 · 2013: 14 · 2012: 19
FWCI
5.94
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA073756, CA75080, CA73756, R01CA075080)
  • National Institute of Allergy and Infectious Diseases (R37AI035098)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
NF-κB, RelA/p65, KRAS, lung cancer, lung carcinogenesis, IKKβ, p53, apoptosis, therapeutic target
MeSH terms
Animals, Cell Transformation, Neoplastic, Humans, Lung Neoplasms, Genes, ras, Transfection, Genes, p53, Tumor Suppressor Protein p53, NF-kappa B, Cell Line, Tumor, Mice, I-kappa B Kinase, Transcription Factor RelA

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