Reduced 15S-lipoxygenase-2 expression in esophageal cancer specimens and cells and upregulation in vitro by the cyclooxygenase-2 inhibitor, NS398.
Alterations in arachidonic acid metabolism are involved in human carcinogenesis. Cyclooxygenase (COX) and lipoxygenase (LOX) are key enzymes in this metabolism. We analyzed the expression of 15S-lipoxygenase-2 (15-LOX-2) mRNA and protein in surgical specimens from normal (N=37) and malignant (63) esophageal tissues using in situ hybridization and immunohistochemistry (IHC), and in normal (1), premalignant (1), and malignant (5) esophageal cell lines using Northern and Western blotting. 15-LOX-2 was expressed in normal esophageal epithelial cells (EECs) at the highest levels, whereas an SV40-immortalized HET-1A line and three of five esophageal cancer cell lines failed to express it at detectable levels. 15-LOX-2 was detected in 76% (28/37) of the normal esophageal mucosae, but only in 46% (29/63) of the cancer specimens using IHC (P<.01). Transient transfection of 15-LOX-2 expression vectors into esophageal cancer cells significantly inhibited the proliferation of 15-LOX-2-negative cancer cells. The COX-2 inhibitor, NS398, induced 15-LOX-2 expression in esophageal cancer cells, which is associated with reduced cell viability. This study demonstrated that 15-LOX-2 expression is lost in esophageal cancers and that the induction of 15-LOX-2 can inhibit cancer cell proliferation. Further investigation of the effects of nonsteroidal anti-inflammatory drugs on 15-LOX-2 expression and apoptosis in esophageal cancer cells may be warranted.
Xu
Xiao-Chun
XC
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. xxu@mdanderson.org
Shappell
Scott B
SB
Liang
Zhengdong
Z
Song
Shumei
S
Menter
David
D
Subbarayan
Vemparala
V
Iyengar
Sunita
S
Tang
Dean G
DG
Lippman
Scott M
SM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics*; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009092:Mucous Membrane / Q000473:pathology; D009578:Nitrobenzenes / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D012313:RNA; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase; D001973:Bromodeoxyuridine