HCAR3 and Kynurenic Acid in Cancer: A Promising Axis of Immunometabolic Regulation or a Scientific Mirage?
Abstract
1. Introduction
2. HCAR3 in Cancer
2.1. Colorectal Cancer
2.2. Breast Cancer
2.3. Acute Myeloid Leukemia (AML)
2.4. Skin Cancer
2.5. Other Types of Cancer
3. The Kynurenine Pathway in Cancer
4. The Possible Interactions Between Kynurenic Acid and HCAR3 in Cancer
5. HCAR3 and Kynurenic Acid in Cancer: Fact or Hypothetical Interaction?
- Most studies to date have focused on HCAR3 gene expression in cancer, rather than its functional activity. Notably, overexpression of HCAR3 is not always correlated with the protein HCAR3 level; however, the regulatory mechanism of this phenomenon has not been studied. Further studies are necessary to indicate post-transcriptional or post-translational regulations involved in this process.
- To validate the hypothesis concerning the role of HCAR3 and KYNA in carcinogenesis, large-scale, multicenter studies employing standardized research protocols and statistical approaches are essential. Available data do not allow us to determine whether the modified expression level of HCAR3 in cancer enhances cancer progression or whether it is a nonspecific effect of altered metabolism of tumor cells. Is there functional compensation at the protein level between HCAR3 and other HCAR receptors?
- Previous research focused only on the interaction between HCAR3 and KYNA without considering the broader context of the kynurenine pathway and other biologically active tryptophan metabolites. It should be verified whether the suggested functional interaction concerns only HCAR3 and KYNA, or whether we should consider a broader metabolic network. Is it possible to verify the molecular and biological effects of KYNA-mediated HCAR3 activation in cancer cells, taking into account the number of KYNA-activated receptors, signaling pathways, and cell cycle regulators? Unfortunately, the lack of HCAR3 antagonists, gene silencing efficiency, occurrence of paralogs, and expression of HCAR3 only in mammalian cells are significant obstacles to carrying out further advanced research.
- The role of HCAR3 should be considered not only as a direct effect on cancer cells, but also in more complex interactions with the tumor microenvironment and the immune system.
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
α7 nAChR | α-7 nicotinic acetylcholine receptor |
AhR | aryl hydrocarbon receptor |
AML | acute myeloid leukemia |
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid |
ESCC | esophageal squamous cell carcinoma |
ER | estrogen receptor |
ERK | extracellular signal-regulated kinase |
HCAR | hydroxycarboxylic acid receptor |
GPCR | G-protein-coupled receptor |
IDO | indoleamine 2,3-dioxygenase |
KYNA | kynurenic acid |
NAD | nicotinamide adenine dinucleotide |
NMDA | N-methyl-d-aspartate receptor |
3-OH | 3-hydroxyoctanoic acid |
PR | progesterone receptor |
TCGA | The Cancer Genome Atlas |
TDO | tryptophan 2,3-dioxygenase |
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Type of Cancer | pTPM Cancer | pTPM Validation | |
---|---|---|---|
Central nervous system cancer | Glioblastoma multiforme | 0.2 (N = 141) | 0.4 (N = 58) |
Lung cancer | Lung adenocarcinoma | 1.5 (N = 497) | 2.8 (N = 105) |
Lung squamous cell carcinoma | 6.5 (N = 489) | 11.3 (N = 68) | |
Gastrointestinal cancer | Colon adenocarcinoma | 0.5 (N = 254) | 3.6 (N = 486) |
Rectum adenocarcinoma | 0.4 (N = 88) | 2.6 (N = 207) | |
Stomach adenocarcinoma | 0.5 (N = 346) | No data available | |
Liver hepatocellular carcinoma | 0.2 (N = 362) | 0.5 (N = 231) | |
Pancreatic adenocarcinoma | 0.5 (N = 176) | 1.5 (N = 80) | |
Urinary tract cancers | Bladder urothelial carcinoma | 8.1 (N = 169) | No data available |
Kidney chromophobe | 1.2 (N = 64) | No data available | |
Kidney renal clear cell carcinoma | 0.2 (N = 521) | 0.4 (N = 100) | |
Kidney renal papillary cell carcinoma | 0.1 (N = 282) | No data available | |
Cancers of the male reproductive system | Prostate adenocarcinoma | 0.4 (N = 480) | No data available |
Testicular germ cell tumor | 0.9 (N = 133) | No data available | |
Cancers of the female reproductive system | Cervical squamous cell carcinoma and endocervical adenocarcinoma | 7.3 (N = 283) | No data available |
Ovary serous cystadenocarcinoma | 0.2 (N = 349) | 0.2 (N = 81) | |
Uterine corpus endometrial carcinoma | 0.1 (N = 176) | No data available | |
Skin cutaneous melanoma | 0.1 (N = 99) | No data available | |
Breast invasive carcinoma | 0.7 (N = 1022) | No data available | |
Head and neck squamous cell carcinoma | 10.5 (N = 492) | No data available |
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Walczak, K.; Krasowska, D. HCAR3 and Kynurenic Acid in Cancer: A Promising Axis of Immunometabolic Regulation or a Scientific Mirage? Int. J. Mol. Sci. 2025, 26, 6269. https://doi.org/10.3390/ijms26136269
Walczak K, Krasowska D. HCAR3 and Kynurenic Acid in Cancer: A Promising Axis of Immunometabolic Regulation or a Scientific Mirage? International Journal of Molecular Sciences. 2025; 26(13):6269. https://doi.org/10.3390/ijms26136269
Chicago/Turabian StyleWalczak, Katarzyna, and Dorota Krasowska. 2025. "HCAR3 and Kynurenic Acid in Cancer: A Promising Axis of Immunometabolic Regulation or a Scientific Mirage?" International Journal of Molecular Sciences 26, no. 13: 6269. https://doi.org/10.3390/ijms26136269
APA StyleWalczak, K., & Krasowska, D. (2025). HCAR3 and Kynurenic Acid in Cancer: A Promising Axis of Immunometabolic Regulation or a Scientific Mirage? International Journal of Molecular Sciences, 26(13), 6269. https://doi.org/10.3390/ijms26136269