Blockade of leukotriene B4 signaling pathway induces apoptosis and suppresses cell proliferation in colon cancer.
We investigated whether leukotriene B(4) (LTB(4)) and its signaling pathway play an important role in the progression of human colon cancer via a direct stimulation of cancer cell proliferation. Remarkable expression of LTB(4) receptor 1 (BLT1) in human colon cancer tissues was detected by immunohistochemistry, and Western blot analysis revealed the BLT1 expression in cultured human colon cancer cell lines, Caco2 and HT29. The 5-lipoxygenase inhibitor AA-861 and LTB(4)-receptor antagonist U75302 showed negative effects on survival and proliferation of both Caco2 and HT-29 cells. The inhibition of cell proliferation is due to the apoptosis because nuclear condensation and increased annexin V expression were observed in the cells treated with AA-861 and U75302. Knockdown of BLT1 by small interfering RNA caused the suppression of BLT1 protein, resulting in the inhibition of cancer cell proliferation. Blockade of BLT1 by the receptor antagonist significantly suppresses the LTB(4)-stimulated extracellular signal-regulated kinase (ERK) activation in colon cancer cells. These results indicate that the blockade of the LTB(4)-signaling pathway induces apoptosis via the inhibition of ERK activation in colon cancer cells. The LTB(4)-signaling pathway might be a new therapeutic target for colon cancer.
Ihara
Aya
A
Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Wada
Koichiro
K
Yoneda
Masato
M
Fujisawa
Nobutaka
N
Takahashi
Hirokazu
H
Nakajima
Atsushi
A
D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology*; D006018:Glycols / Q000494:pharmacology*; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors; D034622:RNA Interference; D018102:Receptors, Leukotriene B4 / Q000032:analysis / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*
D016227:Benzoquinones; D005233:Fatty Alcohols; D006018:Glycols; C513240:LTB4R protein, human; 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; D048049:Extracellular Signal-Regulated MAP Kinases