title: 12/15 Lipoxygenase regulation of colorectal tumorigenesis is determined by the relative tumor levels of its metabolite 12-HETE and 13-HODE in animal models.
abstract: Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. The arachidonic acid (AA) pathway and linoleic acid (LA) pathway have been implicated as important contributors to CRC development and growth. Human 15-lipoxygenase 1 (15-LOX-1) converts LA to anti-tumor 13-S-hydroxyoctadecadienoic acid (13-HODE)and 15-LOX-2 converts AA to 15-hydroxyeicosatetraenoic acid (15-HETE). In addition, human 12-LOX metabolizes AA to pro-tumor 12-HETE. In rodents, the function of 12-LOX and 15-LOX-1 and 15-LOX-2 is carried out by a single enzyme, 12/15-LOX. As a result, conflicting conclusions concerning the role of 12-LOX and 15-LOX have been obtained in animal studies. In the present studies, we determined that PD146176, a selective 15-LOX-1 inhibitor, markedly suppressed 13-HODE generation in human colon cancer HCA-7 cells and HCA-7 tumors, in association with increased tumor growth. In contrast, PD146176 treatment led to decreases in 12-HETE generation in mouse colon cancer MC38 cells and MC38 tumors, in association with tumor inhibition. Surprisingly, deletion of host 12/15-LOX alone led to increased MC38 tumor growth, in association with decreased tumor 13-HODE levels, possibly due to inhibition of 12/15-LOX activity in stroma. Therefore, the effect of 12/15-LOX on colorectal tumorigenesis in mouse models could be affected by tumor cell type (human or mouse), relative 12/15 LOX activity in tumor cells and stroma as well as the relative tumor 13-HODE and 12-HETE levels.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Hepatic Surgery Center,Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Yinqiu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.affiliation: Hepatic Surgery Center,Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.|Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D008041:Linoleic Acids / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D047368:Tumor Burden
chemical_list: C475064:12-15-lipoxygenase; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; C024348:13-hydroxy-9,11-octadecadienoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase