Abstract 4195: Mechanisms involved in the HIF1 mediated acceleration of chemical carcinogenicity

Abstract

Abstract Polycyclic aromatic hydrocarbons (PAHs) are potent carcinogens produced by the incomplete combustion of organic materials. The best studied PAH is the environmentally ubiquitous benzo[a]pyrene (B[a]P) whose mutagenic and carcinogenic potential has been demonstrated in both humans and animals. Recently we have demonstrated that activation of the transcription factor HIF1α amplifies the B[a]P induced mutagenic phenotype. More specifically, HIF1α appears to sequester a critical cofactor for carcinogen detoxification, HIF1β/ARNT. Reducing the availability of this cofactor for coupling with the aryl hydrocarbon receptor (AhR) results in decreased expression of enzymes responsible for detoxifying and removing the carcinogen. The primary mode of HIF1α activation is by low oxygen concentrations. Although not commonly observed in normal tissue, hypoxia can be induced by pathologies such as chronic obstructive pulmonary disease (COPD). Thus hypoxia may offer an attractive explanation for the observed increase in cancer incidence in patients with COPD. A secondary means to stabilize HIF1α is by oncogene activation or tumour suppressor loss. This mechanism is independent of oxygen levels and implies that HIF1α may play an important role in the progression of premalignant cells into a tumour. Although we observe a 3 fold increase in mutation frequency at the hprt locus in cells after B[a]P exposure under hypoxic conditions, the changes in DNA adduct formation are minimal. This suggests that other cellular response pathways are modified concurrently with HIF1α activation. We have identified three important cellular mechanisms that may be responsible for the increase in B[a]P mutagenicity upon HIF1α activation. These are changes to the metabolism of B[a]P; the transmembrane transport of B[a]P or its metabolites; or the capacity to repair the subsequent DNA damage. First, under conditions of low oxygen, the B[a]P-9,10-dihydrodiol metabolites decreased while the B[a]P-7,8-dihydrodiol and 3-OH-B[a]P metabolites are formed in higher quantities compared to normoxia. Furthermore, when HIF was upregulated either by hypoxia (0.2% O2) or CoCl2, the extracellular concentrations of the parent B[a]P compound were dramatically increased compared with cells treated under higher (20% and 5%) oxygen concentrations. And finally, using a modified comet assay to determine the DNA repair capacity, we observe that cells in which HIF1α is dysregulated (VHL mutants) have an approximately 10 fold decrease in the ability to repair B[a]P induced adducts. Taken together, these results show that all three of these processes may in part be responsible for the enhanced mutagenic phenotype under hypoxia. Insight into these pathways may provide further understanding of the intrinsic risks for mutagenic exposures and provide new targets and tools for therapies directed against cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4195. doi:10.1158/1538-7445.AM2011-4195