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

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2299-2310
Number of pages12
JournalOncogene
Volume35
Issue number18
DOIs
StatePublished - May 5 2016

Bibliographical note

Funding Information:
We thank Dr Philip N Tsichlis for providing us the Tpl2?/? 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.

Publisher Copyright:
© 2016 Macmillan Publishers Limited All rights reserved.

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