Loss of VHL in RCC Reduces Repair and Alters Cellular Response to Benzo[a]pyrene.

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 ? (HIF?). 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 HIF? is stabilized regardless of oxygen tension, to 0.1??M BaP for 18?h. The mutagenic BPDE-DNA adduct levels were increased in HIF? 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 HIF? 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.

SUBMITTER: Schults MA 

PROVIDER: S-EPMC3809518 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature