Creatine riboside is a cancer cell–derived metabolite associated with arginine auxotrophy
Amelia L. Parker, … , Xin Wei Wang, Curtis C. Harris
Amelia L. Parker, … , Xin Wei Wang, Curtis C. Harris
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e157410. https://doi.org/10.1172/JCI157410.
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Creatine riboside is a cancer cell–derived metabolite associated with arginine auxotrophy

Abstract

The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell–derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.

Authors

Amelia L. Parker, Leila Toulabi, Takahiro Oike, Yasuyuki Kanke, Daxeshkumar Patel, Takeshi Tada, Sheryse Taylor, Jessica A. Beck, Elise Bowman, Michelle L. Reyzer, Donna Butcher, Skyler Kuhn, Gary T. Pauly, Kristopher W. Krausz, Frank J. Gonzalez, S. Perwez Hussain, Stefan Ambs, Bríd M. Ryan, Xin Wei Wang, Curtis C. Harris

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Figure 3

Creatinine is a metabolic precursor of CR.

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Creatinine is a metabolic precursor of CR. Correlation of CR with creati...
Correlation of CR with creatine (A) and creatinine (B) within NSCLC tumor tissues (Spearman’s correlation; n = 147 tissue samples). (C and D) Fractional enrichment of CR labeling from 13C-creatine or 13C-creatinine in H460 (C) and A549 (D) cells. Data indicate the mean ± SEM of 3 independent experiments. ****P < 0.0001, by 1-way ANOVA with Holm-Šidák correction for multiple comparisons. (E and F) Fractional enrichment of CR labeling from 13C-creatinine or 13C-arginine in H460 cells (E) and A549 cells (F). Data indicate the mean ± SEM of 3 independent experiments. ****P < 0.0001, by 1-way ANOVA with Holm-Šidák correction for multiple comparisons. The 13C-creatinine treatment group is replicated from C and D. (G and H) CR levels increased with increasing creatinine supplementation as measured by the fractional enrichment of CR labeling from 13C-creatinine in H460 (G) and A549 (H) cells. Dotted line indicates endogenous serum levels of creatinine (75 μM) in humans. Data indicate the mean ± SEM of 3 independent experiments. (I) Intracellular CR concentrations in CRlo (blue) and CRhi (red) cell lines with increasing concentrations of exogenously supplied creatinine. Data indicate the mean ± SEM of 3 independent experiments (J) Intracellular creatinine concentrations in CRlo (blue) and CRhi (red) cell lines with increasing concentrations of exogenously supplied creatinine. Data indicate the mean ± SEM of 3 independent experiments. (K) Time course of the fractional enrichment of CR labeling from 13C-creatinine over 72 hours in H460 cells. Data indicate the mean ± SEM of 3 independent experiments.