Acrolein contributes to urothelial carcinomas in patients with chronic kidney disease

Jian-Hua Hong; Priscilla Ann Hweek Lee; Yu-Chuan Lu; Cheng-Yu Huang; Chung-Hsin Chen; Chih-Hung Chiang; Po-Ming Chow; Fu-Shan Jaw; Chung-Chieh Wang; Chao-Yuan Huang; Tse-Wen Wang; Jin-Hui Liu; Hsiang-Tsui Wang

doi:10.1016/j.urolonc.2020.02.017

Acrolein contributes to urothelial carcinomas in patients with chronic kidney disease

Urol Oncol. 2020 May;38(5):465-475. doi: 10.1016/j.urolonc.2020.02.017. Epub 2020 Mar 18.

Authors

Affiliations

¹ Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan, ROC; Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
² Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC.
³ Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
⁴ Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC; Department of Urology, Taipei Veterans General Hospital, Yuanshan Branch, Taipei, Taiwan, ROC.
⁵ Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan, ROC.
⁶ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan, ROC.
⁷ Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, Taipei, Taiwan, ROC.
⁸ Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC. Electronic address: htwang01@ym.edu.tw.

PMID: 32199754
DOI: 10.1016/j.urolonc.2020.02.017

Abstract

Background: Urothelial carcinomas (UCs) are highly prevalent in patients with end-stage renal disease. Chronic kidney disease (CKD) is the predecessor of end-stage renal disease, and it is also associated with UC. However, the interplay between CKD and UC lacks solid evidence. Acrolein is produced by polyamines and has been suggested to be the uremic "toxin." The level of acrolein correlates well with chronic renal failure. We recently found that acrolein-induced DNA damage and inhibited DNA repair in urothelial cells, which contribute to bladder cancer. Therefore, we hypothesize that acrolein is involved in the formation of UC in patients with CKD.

Materials and methods: A total of 62 UC patients and 43 healthy control subjects were recruited. Acrolein-DNA (Acr-dG) adducts and p53 gene mutations in UC tissues, plasma acrolein-protein conjugates (Acr-PC) and S-(3-hydroxypropyl)-N-acetylcysteine levels, and urinary Acr metabolites were analyzed in these patients.

Results: Acr-dG levels were statistically correlated with CKD stages in UC patients (P < 0.01). Most p53 mutations were G to A and G to T mutations in these patients, and 50% of mutations at G:C pairs occurred in CpG sites, which is similar to the mutational spectra induced by Acr-dG adducts. Acr-PC levels in the plasma of UC patients with CKD were significantly higher than those of control subjects (P < 0.001). Altered urinary S-(3-hydroxypropyl)-N-acetylcysteine was also found in UC patients with CKD compared to control subjects (P < 0.005).

Conclusion: These results indicate that acrolein acts as an endogenous uremic toxin and contributes to UC formation in patients with CKD.

Keywords: 3-HPMA; Acrolein; Acrolein-DNA adducts; Acrolein-protein conjugates; Chronic kidney disease; Urothelial carcinomas.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrolein / adverse effects*
Aged
Carcinoma, Transitional Cell / genetics*
DNA Damage*
Female
Genes, p53 / drug effects*
Genes, p53 / genetics*
Humans
Male
Middle Aged
Mutation*
Renal Insufficiency, Chronic / complications*
Tumor Cells, Cultured
Urologic Neoplasms / genetics*

Substances

Acrolein