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Carcinogenesis Advance Access published online on January 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi026
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Oxford University Press
Received August 18, 2004
Revised December 22, 2004
Accepted January 11, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention

Ashraful Hoque 1, Scott M. Lippman 1, Tsung-Teh Wu 2, Ya Xu 1, Zheng D. Liang 1, Stephen Swisher 3, Hongfu Zhang 4, Liyu Cao 4, Jaffer A. Ajani 5, and Xiao-chun Xu 1*

1 Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
2 Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
3 Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
4 Department of Pathology, Anhui Medical University, Hefei, China
5 Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

* To whom correspondence should be addressed.
Xiao-chun Xu, E-mail: xxu{at}mdanderson.org


  Abstract

Arachidonic acid is the major precursor of several classes of signal molecules and alteration of its metabolism is involved in human carcinogenesis. For instance, 5-lipoxygenase (5-LOX) converts arachidonic acid to hydroxyeicosatetraenoic acids or leukotrienes, which are able to enhance proliferation, increase survival, and suppress apoptosis of human cells. To determine the potential use of 5-LOX inhibitors for the prevention of esophageal cancer, we first analyzed 5-LOX expression in esophageal tissue samples using immunohistochemistry and then examined the effect of the 5-LOX inhibitors AA861 and REV5901 on cell viability and apoptosis in esophageal cancer cell lines. 5-LOX expression was present in 79% (127/161) of esophageal cancer but in only 13% (4/32) of normal esophageal mucosa. 5-LOX was also expressed in all eight esophageal cancer cell lines. Moreover, 5-LOX inhibitors caused a dose- and time-dependent reduction of cell viability, which was due to the induction of apoptosis and associated with LTB4 suppression. Our data also showed that both leukotriene B4, a product of 5-LOX, and leukotriene B4 receptor antagonist U-75302 were able to prevent AA861 and REV5901 on induction of apoptosis. The present study demonstrated that 5-LOX protein expression is increased in esophageal cancer and that 5-LOX inhibitors can induce esophageal cancer cells to undergo apoptosis, suggesting that 5-LOX may be effective target in prevention of esophageal cancer.

Keywords: 5-LOX; 5-LOX inhibitors; esophageal cancer; apoptosis; cancer prevention.
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