In a recent study, we showed that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), two common omega-3 fatty acids, can cause ROS accumulation and subsequently induce caspase-8-dependent apoptosis in human breast cancer cells (Kang et al. [2010], PLoS ONE 5: e10296). In this study, we showed that the pancreas has a unique ability to accumulate EPA at a level markedly higher than several other tissues analyzed. Based on this finding, we sought to further investigate the anticancer actions of EPA and its analog DHA in human pancreatic cancer cells using both in vitro and in vivo models. EPA and DHA were found to induce ROS accumulation and caspase-8-dependent cell death in human pancreatic cancer cells (MIA-PaCa-2 and Capan-2) in vitro. Feeding animals with a diet supplemented with 5% fish oil, which contains high levels of EPA and DHA, also strongly suppresses the growth of MIA-PaCa-2 human pancreatic cancer xenografts in athymic nude mice, by inducing oxidative stress and cell death. In addition, we showed that EPA can concomitantly induce autophagy in these cancer cells, and the induction of autophagy diminishes its ability to induce apoptotic cell death. It is therefore suggested that combination of EPA with an autophagy inhibitor may be a useful strategy in increasing the therapeutic effectiveness in pancreatic cancer.
We have previously shown that several polycyclic aromatic hydrocarbons (PAHs) strongly inhibit their own and other PAH metabolism catalyzed by cytochrome P450 (P450) 1A1, 1A2, and 1B1 [Shimada, T., and Guengerich, F. P. (2006) Chem. Res. Toxicol. 19, 288-294]. In the present study, we examined mechanisms of how PAHs inhibit these P450 enzymes by using 7-ethoxyresorufin O-deethylation (EROD) as a model reaction. First, we examined mechanisms of inhibition of P450 1A1, 1A2, and 1B1 by the synthetic model inhibitors 1-(1-propynyl)pyrene (1PP), 1-ethynylpyrene (1EP), 2-ethynylpyrene (2EP), and 4-(1-propynyl)biphenyl (4Pbi). Both 1PP and 1EP inhibited P450 1A1 in a mechanism-based manner, but P450 1B1 and 1A2 were directly inhibited by 1PP and 1EP. Interestingly, P450 1B1 inactivated 1PP and 1EP to products that were not inhibitory to P450 1B1. 4Pbi was a mechanism-based inhibitor of P450 1A1 and 1B1, but 2EP directly inhibited these P450s. All four of the inhibitors directly inhibited P450 1A2. We also found that benzo[a]pyrene and seven other PAH compounds tested inhibited P450 1A2 in a mechanism-based manner, but fluoranthene directly inhibited P450 1A2. All of the nine PAHs examined were direct inhibitors of P450 1A1 and P450 1B1. These results suggest different mechanisms of inhibition of P450 1A1, 1A2, and 1B1 by PAHs and related chemicals and that interactions between P450 enzymes and PAH inhibitors are involved in differences in inhibition of the enzymes.
Bisphenol A [2,2-bis-(4-hydroxyphenyl) propane; BPA] is a versatile industrial material for plastic products, but is increasingly being recognized as a pervasive industrial pollutant as well. Accumulating evidence indicates that the environmental contaminant BPA is one of the endocrine-disrupting chemicals that potentially can adversely affect humans as well as wildlife. To define the molecular aspects of BPA action, we first investigated the molecules with which it physically interacts. High BPA-binding activity was detected in the P2 membrane fraction prepared from rat brains. As determined by SDS-PAGE analysis, the molecular mass of a BPA-binding protein purified from the rat brain P2 fraction was 53 kDa. The N-terminal amino acid sequence of the purified BPA-binding protein was identical with that of the rat protein disulfide isomerase (PDI), which is a multifunctional protein that is critically involved in the folding, assembly, and shedding of many cellular proteins via its isomerase activity in addition to being considered to function as an intracellular hormone reservoir. The Kd value of BPA binding to recombinant rat PDI was 22.6 +/- 6.6 microm. Importantly, the binding activity of L-T3 and 17beta-estradiol hormones to PDI was competitively inhibited by BPA in addition to abolishing its isomerase activities. In this paper we report that the ubiquitous and multifunctional protein PDI is a target of BPA and propose that binding to PDI and subsequent inhibition of PDI activity might be mechanistically responsible for various actions of BPA.
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