The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals

A. Alicia Koblansky, Agnieszka D. Truax, Rongrong Liu, Stephanie A. Montgomery, Shengli Ding, Justin E. Wilson, W. June Brickey, Marcus Mühlbauer, Rita Marie T McFadden, Peizhen Hu, Zengshan Li, Christian Jobin, Pauline Kay Lund, Jenny P Y Ting

Research output: Research - peer-reviewArticle

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Abstract

NOD-like receptor (NLR) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1-/- mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6). The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+ genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+ colon tumorigenesis, cellular proliferation, NF-κB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R) antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1-/-Apcmin/+ mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1.

LanguageEnglish (US)
Pages2562-2575
Number of pages14
JournalCell Reports
Volume14
Issue number11
DOIs
StatePublished - Mar 22 2016

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Colon
Carcinogenesis
Neoplasms
Tumors
Colonic Neoplasms
STAT3 Transcription Factor
Interleukin-6 Receptors
Mitogen-Activated Protein Kinases
Interleukin-6
Chemical activation
Colitis
Transcriptional Activation
Therapeutics
Antibodies
Sensors
Proteins
STAT6 Transcription Factor
Gastrointestinal Neoplasms
Genetic Models
Tumor Burden

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. / Koblansky, A. Alicia; Truax, Agnieszka D.; Liu, Rongrong; Montgomery, Stephanie A.; Ding, Shengli; Wilson, Justin E.; Brickey, W. June; Mühlbauer, Marcus; McFadden, Rita Marie T; Hu, Peizhen; Li, Zengshan; Jobin, Christian; Lund, Pauline Kay; Ting, Jenny P Y.

In: Cell Reports, Vol. 14, No. 11, 22.03.2016, p. 2562-2575.

Research output: Research - peer-reviewArticle

Koblansky, AA, Truax, AD, Liu, R, Montgomery, SA, Ding, S, Wilson, JE, Brickey, WJ, Mühlbauer, M, McFadden, RMT, Hu, P, Li, Z, Jobin, C, Lund, PK & Ting, JPY 2016, 'The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals' Cell Reports, vol 14, no. 11, pp. 2562-2575. DOI: 10.1016/j.celrep.2016.02.064
Koblansky AA, Truax AD, Liu R, Montgomery SA, Ding S, Wilson JE et al. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. Cell Reports. 2016 Mar 22;14(11):2562-2575. Available from, DOI: 10.1016/j.celrep.2016.02.064
Koblansky, A. Alicia ; Truax, Agnieszka D. ; Liu, Rongrong ; Montgomery, Stephanie A. ; Ding, Shengli ; Wilson, Justin E. ; Brickey, W. June ; Mühlbauer, Marcus ; McFadden, Rita Marie T ; Hu, Peizhen ; Li, Zengshan ; Jobin, Christian ; Lund, Pauline Kay ; Ting, Jenny P Y. / The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. In: Cell Reports. 2016 ; Vol. 14, No. 11. pp. 2562-2575
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