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Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene
Marten A Schults1, Yvonne Oligschlaeger, Roger W Godschalk
1Department of Toxicology, Maastricht University Medical Centre, NUTRIM-School for Nutrition, Toxicology and Metabolism, Maastricht University , Maastricht , Netherlands.
Abstract:
Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur in the majority of sporadic renal-cell carcinomas (RCC). Loss of VHL function is associated with stabilization of hypoxia-inducible factor α (HIFα). We and others demonstrated that there is a two-way interaction between the aryl hydrocarbon receptor, which is an important mediator in the metabolic activation and detoxification of carcinogens, and the HIF1-pathway leading to an increased genetic instability when both pathways are simultaneously activated. The aim of this study was to investigate how environmental carcinogens, such as benzo[a]pyrene (BaP), which can be metabolically activated to BaP-7,8-diOH-9,10-epoxide (BPDE) play a role in the etiology of RCC. We exposed VHL-deficient RCC4 cells, in which HIFα is stabilized regardless of oxygen tension, to 0.1 μM BaP for 18 h. The mutagenic BPDE-DNA adduct levels were increased in HIFα stabilized cells. Using qRT-PCR, we demonstrated that absence of VHL significantly induced the mRNA levels of AhR downstream target CYP1A1. Furthermore, HPLC analysis indicated that loss of VHL increased the concentration of BaP-7,8-dihydroxydiol, the pre-cursor metabolite of BPDE. Interestingly, the capacity to repair BPDE-DNA adducts in the HIFα stabilized RCC4 cells, was markedly reduced. Taken together, these data indicate that loss of VHL affects BaP-mediated genotoxic responses in RCC and decreases repair capacity.
Insights
Loss of VHL function in renal cell carcinoma (RCC) increases DNA damage from environmental carcinogens like benzo[a]pyrene. This VHL deficiency also impairs the cells' ability to repair this damage, contributing to cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Environmental Health
Background:
- Mutations in the von Hippel-Lindau (VHL) gene are common in sporadic renal cell carcinoma (RCC).
- VHL loss stabilizes hypoxia-inducible factor α (HIFα), a pathway interacting with the aryl hydrocarbon receptor (AhR).
- Simultaneous activation of AhR and HIF pathways can increase genetic instability.
Purpose of the Study:
- To investigate the role of environmental carcinogens, specifically benzo[a]pyrene (BaP), in the etiology of RCC.
- To determine how VHL deficiency and HIFα stabilization affect cellular responses to BaP exposure.
Main Methods:
- VHL-deficient RCC4 cells with stabilized HIFα were exposed to benzo[a]pyrene (BaP).
- Quantified mutagenic BPDE-DNA adduct levels.
- Measured mRNA levels of AhR downstream target CYP1A1 using qRT-PCR.
- Analyzed BaP metabolite concentrations using HPLC.
- Assessed the capacity to repair BPDE-DNA adducts.
Main Results:
- Mutagenic BPDE-DNA adduct levels were elevated in HIFα-stabilized cells.
- VHL deficiency significantly increased CYP1A1 mRNA levels.
- Loss of VHL increased the concentration of BaP precursor metabolites.
- The repair capacity for BPDE-DNA adducts was markedly reduced in VHL-deficient cells.
Conclusions:
- Loss of VHL function in RCC influences genotoxic responses to BaP.
- VHL deficiency impairs the cellular DNA repair capacity for carcinogen-induced damage.
- These findings highlight a mechanism linking VHL mutations, environmental exposures, and RCC development.
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