Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention.
Arachidonic acid (AA) is the major precursor of several classes of signal molecules and the alteration of its metabolism is involved in human carcinogenesis. For instance, 5-lipoxygenase (5-LOX) converts AA to hydroxyeicosatetraenoic acids or leukotrienes (LTs), which are able to enhance proliferation, increase survival and suppress the apoptosis of human cells. To determine the potential use of 5-LOX inhibitors in the prevention of esophageal cancer, we first analyzed the 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 the 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 LTB4, a product of 5-LOX and LTB4 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 an effective target in the prevention of esophageal cancer.
Hoque
Ashraful
A
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lippman
Scott M
SM
Wu
Tsung-Teh
TT
Xu
Ya
Y
Liang
Zheng D
ZD
Swisher
Stephen
S
Zhang
Hongfu
H
Cao
Liyu
L
Ajani
Jaffer A
JA
Xu
Xiao-Chun
XC
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D017209:Apoptosis / Q000187:drug effects*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D004947:Esophagus / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology; D005260:Female; D006018:Glycols / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D005233:Fatty Alcohols; D006018:Glycols; D016859:Lipoxygenase Inhibitors; D018102:Receptors, Leukotriene B4; C062137:U 75302; D007975:Leukotriene B4; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase