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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Research Article Oncology

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 5

CR is associated with activation of the PPP and urea cycle dysfunction.

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CR is associated with activation of the PPP and urea cycle dysfunction. ...
(A and B) GSEA of non–small cell lung tumor transcriptional data identified metabolic pathways that were downregulated in CRhi tumors (A) and enriched in CRhi tumors (B) compared with CRlo tumors. Black bars: –log10(P values were adjusted for multiple comparisons); red dots: normalized enrichment score (NES). (C–H) Pathway GSVA of pentose phosphate (C and D), arginine (E and F), and mitochondrial urea cycle (G and H) metabolic pathways in CRhi tumors (lung, n = 44; liver, n = 58) compared with CRlo tumors (lung, n = 43; liver, n = 33) from lung (C, E, and G) and liver (D, F, and H) cancer. *P < 0.05 and ****P < 0.0001, by Mann-Whitney U test. (I–N) CRhi tumors had dysregulated expression of mitochondrial urea cycle enzymes. Downregulation of CPS1 expression as well as that of its cofactor NAGS was seen in NSCLC (I and J) and intrahepatic cholangiocarcinoma (K and L), while HCC had significant upregulation of CPS1 relative to OTC (M and N). *P < 0.05, by Mann-Whitney U test.