title: Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10.
abstract: Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5 μM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-l-cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real-time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen-activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: matsunagat@gifu-pu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Morikawa
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Haga
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Laboratory of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.affiliation: Laboratory of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Victoria 3052, Australia.
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
authors.affiliation: Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000449:Aldehyde Reductase / Q000096:biosynthesis* / Q000235:genetics; D000074408:Aldo-Keto Reductases; D045744:Cell Line, Tumor; D018450:Disease Progression; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010616:Phenanthrenes / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D010616:Phenanthrenes; C005399:9,10-phenanthrenequinone; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase
keywords: 9,10-Phenanthrenequinone; Aldo-keto reductase 1B10; Lung cancer; Malignant progression; Reactive oxygen species