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

Abstract

SUMMARYNOD-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.

NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

“…In addition to our current findings, prior studies have also evaluated NLRX1 in cancer utilizing either xenograft models or models of inflammation driven colorectal cancer [16, 17, 25, 26]. In the xenograft study, nude mice were injected with RKO colon carcinoma cells, where NLRX1 was either stably knocked down or overexpressed [16].…”

“…In the presence of TNF, NLRX1 knockdown resulted in significantly increased tumor volume, whereas overexpression attenuated tumor growth [16]. To evaluate the role of NLRX1 in CAC, tumorigenesis was induced in wild type and Nlrx1 −/− mice by treating the animals with the chemical carcinogen azoxymethane (AOM) immediately prior to dextran sulfate sodium (DSS) exposure [17, 25, 26]. In this model, inflammation associated with DSS exposure functions as a tumor promoter.…”

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

“…However, recent studies have emerged that reveal a more dynamic role for NLRX1 in modulating pathological conditions that extend beyond specific host-pathogen interactions (11, 18, 32). To date, there have been very few studies evaluating NLRX1 function in the CNS.…”

The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production

“…For example, recent evidence has suggested that NLRC3 can also act as a negative regulator of the PI3K-mTOR pathway in epithelial cells, which is involved in colorectal carcinogenesis(26) as well as affecting the type I interferon and proinflammatory pathways. Likewise, NLRX1 has been shown to be involved in negatively regulating multiple tumorigenic pathways(27–29) as well as other inflammatory pathways(23, 28, 30–32). These recent advances in the field have challenged the model that single NLR proteins are pathogen or pathway specific.…”