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NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function

Oncogene volume 35, pages 2299–2310 (2016)Cite this article

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Abstract

Nuclear factor-κB (NF-κB) is generally believed to be pro-tumorigenic. Here we report a tumor-suppressive function for NF-κB1, the prototypical member of NF-κB. While NF-κB1 downregulation is associated with high lung cancer risk in humans and poor patient survival, NF-κB1-deficient mice are more vulnerable to lung tumorigenesis induced by the smoke carcinogen, urethane. Notably, the tumor-suppressive function of NF-κB1 is independent of its classical role as an NF-κB factor, but instead through stabilization of the Tpl2 kinase. NF-κB1-deficient tumors exhibit ‘normal’ NF-κB activity, but a decreased protein level of Tpl2. Reconstitution of Tpl2 or the NF-κB1 p105, but not p50 (the processed product of p105), inhibits the tumorigenicity of NF-κB1-deficient lung tumor cells. Remarkably, Tpl2-knockout mice resemble NF-κB1 knockouts in urethane-induced lung tumorigenesis. Mechanistic studies indicate that p105/Tpl2 signaling is required for suppressing urethane-induced lung damage and inflammation, and activating mutations of the K-Ras oncogene. These studies reveal an unexpected, NF-κB-independent but Tpl2-depenednt role of NF-κB1 in lung tumor suppression. These studies also reveal a previously unexplored role of p105/Tpl2 signaling in lung homeostasis.

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Acknowledgements

We thank Dr Philip N Tsichlis for providing us the Tpl2Δ/Δ mice. This study was supported in part by the National Institute of Health (NIH)/National Cancer Institute (NCI) grants R01 CA172090, R21 CA175252, R21 CA189703, P30 CA047904 and P50 CA090440-Lung Cancer Developmental Research Award, as well as the American Lung Association (ALA) Lung Cancer Discovery Award and American Cancer Society (ACS) Fellowship PF-12-081-01-TBG.

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Author notes

  1. J M Siegfried

    Present address: 5Current address: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.,

Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    F Sun, Z Qu, Y Xiao, J Zhou, T F Burns, L P Stabile, J M Siegfried & G Xiao

  2. Department of Microbiology and Molecular Genetics, Hillman Cancer Center Research Pavilion, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    F Sun, Z Qu, J Zhou & G Xiao

  3. Program of Biological Science, La Roche College, Pittsburgh, PA, USA

    Y Xiao

  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    L P Stabile & J M Siegfried

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Correspondence to Z Qu or G Xiao.

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Sun, F., Qu, Z., Xiao, Y. et al. NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function. Oncogene 35, 2299–2310 (2016). https://doi.org/10.1038/onc.2015.299

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