IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis

Abstract

The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of b-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing b-catenin-stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear b-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of b-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.Significance: This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

“…Here, however, we demonstrate that Kyn plays a cell-autonomous role in maintaining colon cancer cell proliferation. Indeed, a recent study demonstrated that conditional knockout of the IDO1 gene specifically in colonic cells limits colon cancer development in mice (Bishnupuri et al 2019).…”

“…In colorectal cancer, IDO1 expression correlates with reduced tumor infiltration by lymphocytes, increased rates of hepatic metastases, and a poor clinical outcome (Brandacher et al 2006). Recently, it was shown that conditional deletion of IDO1 in colonic cells delays colon cancer in animal models (Bishnupuri et al 2019), indicating that Kyn levels are likely altered in colon cancer and may contribute to tumorigenesis.…”

Expression profile and bioinformatics analysis of circular RNA in intestinal mucosal injury and repair after severe burns

“…Moreover, signaling pathways such as Ras signaling pathway, MAPK signaling pathway, PI3K‐Akt signaling pathway, autophagy, JAK‐STAT signaling pathway and TGF‐β signaling pathway were also identified in the enrichment results. These pathways are critical and participate in a variety of cellular biology processes: the Ras signaling pathway directs cell migration and mediates cell apoptosis (Charest et al, 2010; Gulbins et al, 1995); the MAPK signaling pathway and PI3K‐Akt signaling pathway can promote cell proliferation (Bishnupuri et al, 2019; Y. Wang et al, 2011; Wu, Tan, Huang, Ong, & Shen, 2009); autophagy can alleviate intestinal damage caused by severe burns (D. Zhang, Qiu, Wang, et al, 2017), and the JAK‐STAT signaling pathway involves in promoting migration of intestinal epithelial cells (Le et al, 2016). Understanding the characterization of mRNAs helps us to study the function and characteristics of circRNAs.…”

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

“…[ 177 ] Kynurenine is known to promote intestinal epithelial proliferation and has been linked to inflammation, immune suppression, metabolic disease, psychiatric disorders, and even cancer. [ 178,179 ] Thus, it is interesting to speculate that increased gut microbiale tryptophan metabolism might actually be beneficial for healthy aging by counteracting the hyper‐proliferative effect of host‐derived kynurenine. In fact, a previous report states that indole derivatives produced by commensal bacteria can reduce frailty symptoms in old mice, as well as expand healthspan of worms ( Caenorhabditis elegans ) and flies ( Drosophila melanogaster ).…”