The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis.
Terminal differentiation is an important event for maintaining normal homeostasis in the colorectal epithelium, and the loss of apoptosis is an important mechanism underlying colorectal tumorigenesis. The very limited current data on the role of lipoxygenase (LOX) metabolism in tumorigenesis suggests that the oxidative metabolism of linoleic and arachidonic acid possibly shifts from producing antitumorigenic 15-LOX-1 and 15-LOX-2 products to producing protumorigenic 5-LOX and 12-LOX products. We examined whether this shift occurs in vitro in the human colon cancer cell line Caco-2 in association with the loss of terminal differentiation and apoptosis, or in vivo during the formation of colorectal adenomas in patients with familial adenomatous polyposis (FAP). Restoring terminal differentiation and apoptosis of Caco-2 cells increased the mRNA levels of 5-LOX, 15-LOX-2, and 15-LOX-1, but the only significant increases in protein expression and enzymatic activity were of 15-LOX-1. In FAP patients, 15-LOX-1 expression and activity were significantly down-regulated in adenomas (compared with paired nonneoplastic epithelial mucosa), whereas 5-LOX and 15-LOX-2 protein expressions and enzymatic activities were not. We conducted a validation study with immunohistochemical testing in a second group of FAP patients; 15-LOX-1 expression was down-regulated in colorectal adenomas (compared with nonneoplastic epithelial mucosa) in 87% (13 of 15) of this group. We confirmed the mechanistic relevance of these findings by demonstrating that ectopically restoring 15-LOX-1 expression reestablished apoptosis in Caco-2 cells. Therefore, 15-LOX-1 down-regulation rather than a shift in the balance of LOXs is likely the dominant alteration in LOX metabolism which contributes to colorectal tumorigenesis by repressing apoptosis.
Shureiqi
Imad
I
Department of Clinical Cancer Prevention, the University of Texas MD Anderson Cancer Center, Houston, 77030, USA. ishureiqi@mdanderson.org
Wu
Yuanqing
Y
Chen
Dongning
D
Yang
Xiu L
XL
Guan
Baoxiang
B
Morris
Jeffrey S
JS
Yang
Peiying
P
Newman
Robert A
RA
Broaddus
Russell
R
Hamilton
Stanley R
SR
Lynch
Patrick
P
Levin
Bernard
B
Fischer
Susan M
SM
Lippman
Scott M
SM
D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000473:pathology; D017209:Apoptosis; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D018938:Caco-2 Cells / Q000201:enzymology / Q000473:pathology; D002454:Cell Differentiation; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003106:Colon / Q000201:enzymology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008041:Linoleic Acids / Q000378:metabolism; D013058:Mass Spectrometry; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D008041:Linoleic Acids; D012333:RNA, Messenger; C024348:13-hydroxy-9,11-octadecadienoic acid; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase