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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 andmore » 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. - Highlights: • 9,10-PQ promotes invasion, metastasis and tumorigenicity in lung cancer cells. • The 9,10-PQ-elicited promotion is possibly due to AKR1B10 up-regulation. • AKR1B10 acts as a key regulator for MMP2 induction via activation of MAPK cascade. • AKR1B10 is a predominant reductase involved in redox-cycling of 9,10-PQ in the cells.« less

Authors:
 [1]; ; ;  [1]; ;  [2];  [3];  [4];  [1];  [5]
  1. Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan)
  2. Laboratory of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650 (Japan)
  3. Monash Institute of Pharmaceutical Sciences, Monash University, Victoria 3052 (Australia)
  4. Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181 (Japan)
  5. Faculty of Engineering, Gifu University, Gifu 501-1193 (Japan)
Publication Date:
OSTI Identifier:
22439789
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 278; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; APOPTOSIS; BENZOQUINONES; COMPARATIVE EVALUATIONS; CONCENTRATION RATIO; CYSTEINE; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO; INHALATION; LUNGS; MESSENGER-RNA; METASTASES; NEOPLASMS; OXIDOREDUCTASES; POLYMERASE CHAIN REACTION; SECRETION

Citation Formats

Matsunaga, Toshiyuki, E-mail: matsunagat@gifu-pu.ac.jp, Morikawa, Yoshifumi, Haga, Mariko, Endo, Satoshi, Soda, Midori, Yamamura, Keiko, El-Kabbani, Ossama, Tajima, Kazuo, Ikari, Akira, and Hara, Akira. Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.04.024.
Matsunaga, Toshiyuki, E-mail: matsunagat@gifu-pu.ac.jp, Morikawa, Yoshifumi, Haga, Mariko, Endo, Satoshi, Soda, Midori, Yamamura, Keiko, El-Kabbani, Ossama, Tajima, Kazuo, Ikari, Akira, & Hara, Akira. Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10. United States. doi:10.1016/J.TAAP.2014.04.024.
Matsunaga, Toshiyuki, E-mail: matsunagat@gifu-pu.ac.jp, Morikawa, Yoshifumi, Haga, Mariko, Endo, Satoshi, Soda, Midori, Yamamura, Keiko, El-Kabbani, Ossama, Tajima, Kazuo, Ikari, Akira, and Hara, Akira. Tue . "Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10". United States. doi:10.1016/J.TAAP.2014.04.024.
@article{osti_22439789,
title = {Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10},
author = {Matsunaga, Toshiyuki, E-mail: matsunagat@gifu-pu.ac.jp and Morikawa, Yoshifumi and Haga, Mariko and Endo, Satoshi and Soda, Midori and Yamamura, Keiko and El-Kabbani, Ossama and Tajima, Kazuo and Ikari, Akira and Hara, Akira},
abstractNote = {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. - Highlights: • 9,10-PQ promotes invasion, metastasis and tumorigenicity in lung cancer cells. • The 9,10-PQ-elicited promotion is possibly due to AKR1B10 up-regulation. • AKR1B10 acts as a key regulator for MMP2 induction via activation of MAPK cascade. • AKR1B10 is a predominant reductase involved in redox-cycling of 9,10-PQ in the cells.},
doi = {10.1016/J.TAAP.2014.04.024},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 278,
place = {United States},
year = {Tue Jul 15 00:00:00 EDT 2014},
month = {Tue Jul 15 00:00:00 EDT 2014}
}