Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Because of the lack of reliable prognostic and predictive biomarkers for CRC, most patients are often diagnosed at a late stage. The tryptophan–kynurenine pathway plays a crucial role in promoting cancer progression. Kynurenine is considered an oncometabolite in colon cancer, and its downstream metabolites are also associated with CRC. Kynurenine 3-monooxygenase (KMO), a pivotal enzyme that catalyzes kynurenine metabolism, is essential for several cellular processes. In the current study, we explored the role of KMO in CRC. Immunohistochemical results showed that KMO was upregulated in CRC tissues relative to paired healthy tissue and polyps. Moreover, CRC patients with higher KMO expression were associated with higher metastasis and poorer survival rates. Knockdown of KMO decreased the expression of cancer stem cell markers, as well as the sphere-forming, migration, and invasion abilities of CRC cells. Additionally, blockade of the enzymatic activity of KMO using an inhibitor suppressed sphere formation and cell motility in CRC cells. These findings suggest the clinical relevance of KMO in CRC tumorigenesis and aggressiveness.

Integrated Molecular Characterization to Reveal the Association between Kynurenine 3-Monooxygenase Expression and Tumorigenesis in Human Breast Cancers

“…In our previous study, the overexpression of KMO was correlated with malignancy by promoting cell proliferation and metastasis in TNBC cells [11]. Elevated KMO levels also led to a poor prognosis in patients with TNBC [15], colorectal cancer [43], and HCC [16]. Taken together, the malignant role of the KMO was reported, which aligns with our findings from using numerous bioinformatics tools.…”

Involvement of Kynurenine Pathway in Hepatocellular Carcinoma

“…Moreover, high surface expression of KMO was detected in cytosol and on the cell membranes of breast cancer tissue specimens, indicating its potential as a treatment target for TNBC [139]. A recent study investigated the correlation between upregulated KMO activity and poor clinical outcomes in colorectal cancer (CRC) patients and demonstrated that KMO inhibition suppressed CRC cell proliferation in vitro [140]. On analysing KMO enzyme expression in 120 matched HCC tissue samples, Jin et al showed that the expression of the KMO enzyme is significantly elevated in HCC tumour tissue compared to adjacent normal liver tissue.…”

Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas

“…There are three main hypotheses with regard to the relevance of active tryptophan catabolism through the KP in the tumor microenvironment [59]: first, overexpression of active IDO from malignant cells may deplete the tryptophan pool, thus inhibiting lymphocyte proliferation and abrogating the anti-tumor immune response [34]; second, active KP metabolism could favor the formation of tryptophan derivates that inhibit the proliferation of cytotoxic lymphocytes and induce their death [35,36]; and third, the KP can lead to the constant formation of NAD + , a coenzyme involved in metabolic and signaling pathways, contributing to the suitability of malignant cells [60]. In accordance with this, KMO is the pivotal enzyme in the KP that leads to NAD + synthesis [61] and is related to poor prognosis in several cancers [58,[62][63][64].…”

“…Furthermore, blocking the KMO surface with a KMO polyclonal antibody reduces migration and invasion of MDA-MB-231 cells [57]. Additionally, inhibition of KMO activity represses colorectal cancer cell migration, invasion, and tumor sphere formation [58].…”

“…In this study, KMO mRNA expression did not affect patient survival, which could be due to the population size. However, KMO overexpression is related to malignancy and poor prognosis in patients with triple-negative breast cancer and colorectal cancer [58,62]. Furthermore, the oncogenic activity of KMO favors the potentiation of β-catenin signaling in an enzymeactivity-independent manner, indicating the role of KMO beyond 3-HK production [62].…”