Causation of human urothelial cancer: there are challenging new data!

Bolt, Hermann M.

doi:10.1007/s00204-014-1339-y

Cited by 3 publications

(2 citation statements)

References 17 publications

(15 reference statements)

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“…It is also one of the most studied components of cigarette smoke and is known for its mutagenic and carcinogenic properties 1 . Its role in lung, breast, prostate, cervical, and liver carcinogenesis is known 2 – 4 , however, epidemiological analyses have not yet clearly documented B[a]P or any other polycyclic aromatic hydrocarbon (PAH) as significant candidates for initiating bladder cancer development 5 . Therefore, the risk that exposure to any of these compounds causes bladder cancer is still discussed 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Verma

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Boland

et al. 2017

Sci Rep

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Benzo[a]pyrene (B[a]P), a well-known polyaromatic hydrocarbon, is known for its lung carcinogenicity, however, its role in bladder cancer development is still discussed. Comparative two-dimensional blue native SDS-PAGE analysis of protein complexes isolated from subcellular fractions of 0.5 µM B[a]P-exposed cells indicated a differential regulation of proteins involved in carbohydrate, fatty acid, and nucleotide metabolism, suggesting a possible metabolic flux redistribution. It appeared that B[a]P exposure led to a repression of enzymes (fructose-bisphosphate aldolase A, glucose-6-phosphate isomerase, lactate dehydrogenase) involved in glycolysis, and an up-regulation of proteins (glucose-6-phosphate 1-dehydrogenase, 6-phosphogluconolactonase) catalyzing the pentose phosphate pathway and one carbon metabolism (10-formyltetrahydrofolate dehydrogenase, bifunctional purine biosynthesis protein). Untargeted metabolomics further supported the proteomic data, a lower concentration of glycolytic metabolite was observed as compared to glutamine, xylulose and fatty acids. The analysis of the glutathione and NADPH/NADP+ content of the cells revealed a significant increase of these cofactors. Concomitantly, we did not observe any detectable increase in the production of ROS. With the present work, we shed light on an early phase of the metabolic stress response in which the urothelial cells are capable of counteracting oxidative stress by redirecting the metabolic flux from glycolysis to pentose phosphate pathway.

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Section: Introductionmentioning

confidence: 99%

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Verma

Pink

Boland

et al. 2017

Sci Rep

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“…Bladder cancer is a classic example of such diseases, with studies reporting occupational exposure as the primary cause of approximately 5–25% of different kinds of bladder tumors . Smoking and exposures to aromatic amines are well-known risk factors; however, different studies have also reported the potential of combustion products as a possible contributor to bladder cancer development. − …”

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Response to 3-Nitrobenzanthrone Exposure in Human Urothelial Cancer Cells

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Verma

Zerries

et al. 2017

Chem. Res. Toxicol.

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A product of incomplete combustion of diesel fuel, 3-nitrobenzanthrone (3-NBA), has been classified as a cancer-causing substance. It first gained attention as a potential urinary bladder carcinogen due to the presence of its metabolite in urine and formation of DNA adducts. The aim of the present study was to characterize the dose-response relationship of 3-NBA in human urothelial cancer cell line (RT4) exposed to concentrations ranging from 0.0003 μM (environmentally relevant) to 80 μM by utilizing toxicological and metabolomic approaches. We observed that the RT4 cells were capable of bioactivation of 3-NBA within 30 min of exposure. Activity measurements of various enzymes involved in the conversion of 3-NBA in RT4 cells demonstrated NAD(P)H:quinone oxidoreductase (NQO1) as the main contributor for its bioactivation. Moreover, cytotoxicity assessment exhibited an initiation of adaptive mechanisms at low dosages, which diminished at higher doses, indicating that the capacity of these mechanisms no longer suffices, resulting in increased levels of intracellular reactive oxygen species, reduced proliferation, and hyperpolarisation of the mitochondrial membrane. To characterize the underlying mechanisms of this cellular response, the metabolism of 3-NBA and metabolomic changes in the cells were analyzed. The metabolomic analysis of the cells (0.0003, 0.01, 0.08, 10, and 80 μM 3-NBA) showed elevated levels of various antioxidants at low concentrations of 3-NBA. However, at higher exposure concentrations, it appeared that the cells reprogrammed their metabolism to maintain the cell homeostasis via activation of pentose phosphate pathway (PPP).

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Highlight report: gene dose response in N-acetylation capacity

Selinski

2017

Arch Toxicol

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Causation of human urothelial cancer: there are challenging new data!

Cited by 3 publications

References 17 publications

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4

Dose-Dependent Response to 3-Nitrobenzanthrone Exposure in Human Urothelial Cancer Cells

Highlight report: gene dose response in N-acetylation capacity

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