Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma

Abstract

Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. Significance: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.

Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

“…Dysregulation of AhR signalling has been involved in many cancer types, but the pro-tumoral or anti-tumoral effect of AhR is largely context-dependent. Overexpression of constitutively active AhR in transgenic mice models has been reported to induce gastric [ 73 ] and hepatocellular [ 74 ] cancer, whereas decreased AhR activity promotes neuroblastoma metastasis [ 75 ]. Here, through the study of the candidate driver mutation AHR Q383H, we provided a validation of the accuracy of our prediction.…”

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Activation of AhR by kynurenine has also been reported to inhibit the growth of tumor cells, promote cellular differentiation, and decrease the formation of hepatic and pulmonary metastases in mice through activation of the tumor suppressor gene KISS1 [55].…”

Diabetes mellitus type 2 drives metabolic reprogramming to promote pancreatic cancer growth

“…This documents for the first time that DM2 impacts on these pathways and that metformin can suppress the tumor by correcting the metabolic deregulation of these pathways. It has been shown that KYN can cause the activation of aryl hydrocarbon receptor (AHR) to inhibit cell proliferation and promote cell differentiation [ 33 ]. KYN treatment can lead to the elevation of tumor metastasis suppressor KISS1, a molecule induced by AHR, to inhibit metastasis [ 33 ].…”

“…It has been shown that KYN can cause the activation of aryl hydrocarbon receptor (AHR) to inhibit cell proliferation and promote cell differentiation [ 33 ]. KYN treatment can lead to the elevation of tumor metastasis suppressor KISS1, a molecule induced by AHR, to inhibit metastasis [ 33 ]. In addition, AHR plays a role in the regulation of body mass in mice fed a Western diet [ 34 ].…”