Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

Chen, Ya Yin; Chung, Jing Gung; Wu, Hsiu Ching; Bau, Da Tian; Wu, Kaung-Hsiung; Kao, Shung Te; Hsiang, Chien Yun; Ho, Tin Yun; Chiang, Su‐Yin

doi:10.3892/or_00000839

Cited by 22 publications

(9 citation statements)

References 55 publications

(72 reference statements)

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“…DNA adducts of AA induces lesion site structural perturbations and conformational heterogeneity of damaged DNA 40 . Moreover, AA exposure leads to suppress DNA repair 41 . In this study, we speculated 20.91% patients harboring AA exposure in UTUC and none in UCB according to rate of AA signature, which may explain the reason why the clonal and subclonal mutation numbers in UTUC were higher than those in UCB.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Yang

Liu³

et al. 2021

The Oncologist

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Background. Different genomic characterization in urothelial carcinoma (UC) by site of origin, may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity. Materials and Methods. We prospectively sequenced 118 tumors and matched blood DNA from Chinese UC patients using next-generation sequencing (NGS) techniques, including 45 UTUC and 73 UCB. 226 UTUC and 350 UCB patients for TCGA were acquired from the cbioportal. Results. There were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort.Compared to UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. UTUC patients had lower PD-L1 than UCB patients. There was no significant difference in the number of DDR mutations, copy number variation (CNV) counts, and tumor mutational burden (TMB) between UTUC and UCB. Conclusions. UTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB. The Oncologist ;9999:• • Implications for Practice: Our findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between UTUC and UCB and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Yang

Liu³

et al. 2021

The Oncologist

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“…For example, BRCA1 and BRCA2 respond to DNA damage (e.g., double-strand breaks) by interacting with the repair protein RAD-51 [80,81]. Previous in vitro studies demonstrated the formation of double-strand breaks following AA exposure [82]. Our recent work also showed that expression of H2ax, a marker for double-strand breaks, is highest in AAI-exposed Trp53(-/-) kidneys [31].…”

Section: Discussionmentioning

confidence: 64%

The Impact of p53 on Aristolochic Acid I-Induced Gene Expression In Vivo

Sborchia

Keun

Phillips

et al. 2019

IJMS

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Exposure to aristolochic acid (AA) is linked to kidney disease and urothelial cancer in humans. The major carcinogenic component of the AA plant extract is aristolochic acid I (AAI). The tumour suppressor p53 is frequently mutated in AA-induced tumours. We previously showed that p53 protects from AAI-induced renal proximal tubular injury, but the underlying mechanism(s) involved remain to be further explored. In the present study, we investigated the impact of p53 on AAI-induced gene expression by treating Trp53(+/+), Trp53(+/-), and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for six days. The Clariom™ S Assay microarray was used to elucidate gene expression profiles in mouse kidneys after AAI treatment. Analyses in Qlucore Omics Explorer showed that gene expression in AAI-exposed kidneys is treatment-dependent. However, gene expression profiles did not segregate in a clear-cut manner according to Trp53 genotype, hence further investigations were performed by pathway analysis with MetaCore™. Several pathways were significantly altered to varying degrees for AAI-exposed kidneys. Apoptotic pathways were modulated in Trp53(+/+) kidneys; whereas oncogenic and pro-survival pathways were significantly altered for Trp53(+/-) and Trp53(-/-) kidneys, respectively. Alterations of biological processes by AAI in mouse kidneys could explain the mechanisms by which p53 protects from or p53 loss drives AAI-induced renal injury in vivo.

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“…Nevertheless, the observed p21 induction was higher at 12 days than what was found in this study at 6 days, potentially indicating that prolonged treatment with AAI is required to detect significant changes in p21 expression. AAI has also been shown to induce the formation of DNA strand breaks in cells and H2ax is used as a marker for double-strand breaks (Chen et al 2010; Dickey et al 2009). In the present study, H2ax induction was highest in kidneys of AAI-treated Trp53 (−/−) mice, thus going in hand with the proximal tubular injury observed in such tissues.…”

Section: Discussionmentioning

confidence: 99%

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

et al. 2019

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Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(−/−) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography–mass spectrometry (GC–MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice and exposed them to AAI in vitro (50 μM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(−/−) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(−/−) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

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Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

Cited by 22 publications

References 55 publications

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

The Impact of p53 on Aristolochic Acid I-Induced Gene Expression In Vivo

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

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