Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

Abstract

T he aldo-keto reductase (AKR) superfamily includes a group of monomeric 37-kDa soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that function in elimination reactions by modifying carbonyl groups on aldehyde or ketones to form primary or secondary alcohols, which are then conjugated with sulfates or glucuronide for excretion. [1][2][3][4][5][6] Like the cytochrome P450 superfamily, the AKRs are classifi ed as a phase 1 drug, xenobiotic and carcinogen-metabolizing enzymes. 7 One of the Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy IndividualsRui Wang , MD , PhD ; Guoqing Wang , PhD ; Megan J. Ricard , MS ; Barbara Ferris , BA ; Yael Strulovici-Barel , MSc ; Jacqueline Salit , MS ; Neil R. Hackett , PhD ; Lorraine J. Gudas , PhD ; and Ronald G. Crystal Background: The aldo-keto reductase (AKR) gene superfamily codes for monomeric, soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that mediate elimination reactions. AKR1B10, an AKR that eliminates retinals, has been observed as upregulated in squamous metaplasia and non-small cell lung cancer and has been suggested as a diagnostic marker specifi c to tobacco-related carcinogenesis. We hypothesized that upregulation of AKR1B10 expression may be initiated in healthy smokers prior to the development of evidence of lung cancer. Methods: Expression of AKR1B10 was assessed at the mRNA level using microarrays with TaqMan confi rmation in the large airway epithelium (21 healthy nonsmokers, 31 healthy smokers) and small airway epithelium (51 healthy nonsmokers, 58 healthy smokers) obtained by fi beroptic bronchoscopy and brushing. Results: Compared with healthy nonsmokers, AKR1B10 mRNA levels were signifi cantly upregulated in both large and small airway epithelia of healthy smokers. Consistent with the mRNA data, AKR1B10 protein was signifi cantly upregulated in the airway epithelium of healthy smokers as assessed by Western blot analysis and immunohistochemistry, with AKR1B10 expressed in both differentiated and basal cells. Finally, cigarette smoke extract mediated upregulation of AKR1B10 in airway epithelial cells in vitro, and transfection of AKR1B10 into airway epithelial cells enhanced the conversion of retinal to retinol. Conclusions: Smoking per se mediates upregulation of AKR1B10 expression in the airway epithelia of healthy smokers with no evidence of lung cancer. In the context of these observations and the link of AKR1B10 to the metabolism of retinals and to lung cancer, the smoking-induced upregulation of AKR1B10 may be an early process in the multiple events leading to lung cancer.

POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes

“…The BCi-NS1.1 immortalized human airway basal cell line has been reported previously 12 . The effect of cigarette smoke on gene expression was assessed on ALI model with CSE exposure, as described previously 13,14 .…”

Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells

“…In human colon carcinoma cells (HCT-8) and lung carcinoma cells (NCI-H460), siRNA (small-interfering RNA)-induced AKR1B10 silencing results in carbonyl sensitivity and apoptotic cell death secondary to lipid depletion and mitochondrial dysfunction [3,4]. In the airway epithelium, AKR1B10 is up-regulated by cigarette smoke and may activate procarcinogens in smoke, such as polycyclic aromatic hydrocarbons [19][20][21]. Therefore AKR1B10 plays a critical role in cell transformation, growth and survival.…”

AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products

“…If o-quinones and the ROS they generate are not eliminated, they can potentially cause covalent and oxidative DNA lesions, increasing the mutational load of PAH-exposed cells. Together, this sequence of events may contribute to PAH-induced oral carcinogenesis and other malignancies [15,23,25,[53][54][55]58,59,62].…”

“…It is known that, in order to minimize the insults caused by cigarette smoke toxicants and other xenobiotics, various tissues are equipped with diverse Phase I (cytochrome p450, CYP) [45,56,57] and Phase II (AKR) [16,21,25,45,50,58] enzymes which are present in abundance either at the basal level or after induction following xenobiotic exposure. Xenobiotics can be conjugated and eliminated by reduction of their carbonyl groups; however, the same reactions can lead to the activation of a pro-drug as well as the inactivation of a drug [17].…”

“…Xenobiotics can be conjugated and eliminated by reduction of their carbonyl groups; however, the same reactions can lead to the activation of a pro-drug as well as the inactivation of a drug [17]. On one hand, AKR1C isozymes protect against the harmful effects of reactive oxygen species (ROS), since they catalyze the reduction of 4-hydroxy-2-nonenal, a product of lipid peroxidation [21,52,58]. On the other hand, induced AKR1C isozymes can convert PAH trans-dihydrodiols produced by CYPs to deleterious o-quinones via their dihydrodiol dehydrogenase activity [19,22,23,50].…”