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: Toshiyuki Matsunaga, Yoshifumi Morikawa, Mariko Haga, Satoshi Endo, Midori Soda, Keiko Yamamura, Ossama El-Kabbani, Kazuo Tajima, Akira Ikari, Akira Hara
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 278 Issue 2 Pg. 180-9 (Jul 15 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 24813866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Phenanthrenes
• 9,10-phenanthrenequinone
• AKR1B10 protein, human
• Aldo-Keto Reductases
• Aldehyde Reductase

Topics

• Aldehyde Reductase (biosynthesis, genetics)
• Aldo-Keto Reductases
• Cell Line, Tumor
• Disease Progression
• HEK293 Cells
• Humans
• Lung Neoplasms (enzymology, pathology)
• Phenanthrenes (toxicity)
• Up-Regulation (drug effects, physiology)