Carcinogenesis, Vol. 20, No. 10, 1985-1995,
October 1999
© 1999 Oxford University Press
Carcinogenesis |
Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers
1 Division of Hematology and Oncology, Department of Internal Medicine,
2 Department of Pathology,
3 Department of Radiation Oncology,
4 Department of Pharmacology and
5 Biostatistic Core, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109,
6 The Ann Arbor Veteran Affairs Medical Center, 2215 Fuller Avenue, Ann Arbor, MI 48105,
7 Oxford Biomedical Research Inc., 2165 Avon Industrial Drive, Rochester Hills, MI 48309 and
8 The Howard Hughes Medical Institute, Ann Arbor, MI 48109, USA
13-S-Hydroxyoctadecadienoic acid (13-S-HODE), the product of 15-lipoxygenase (15-LOX) metabolism of linoleic acid, enhances cellular mitogenic responses to certain growth factors. Other observations have questioned whether 13-S-HODE has tumorigenic effects. Our study evaluated the hypothesis that 15-LOX-1 is overexpressed in colon cancers resulting in an increase in intracellular 13-S-HODE. 15-LOX-1 and 13-S-HODE were quantified using western blots, ELISA and immunohistochemistry in 18 human colon cancers with paired normal colonic mucosa. Additionally, 15-LOX-1 expression was measured by western blots in three transformed colonic cell lines and in a human umbilical vein endothelial cell line. Next, we evaluated 13-S-HODE effects on cellular proliferation, cell cycle distribution and apoptosis in a transformed colonic cell line (RKO). Cell cycle distributions were measured by flow cytometry and apoptosis was assessed by phase contrast microscopy, electron microscopy, flow cytometry and DNA fragmentation assay. 15-LOX-1 immunohistochemistry staining scores were reduced in tumor tissues (P 
0.0001) and 15-LOX-1 expression was absent in three transformed colonic cell lines. 13-S-HODE levels were also reduced in tumors tissues compared with normal controls by ELISA (median 3.3-fold, P = 0.02) and by immunohistochemistry (P 0.0001). In vitro 13-S-HODE inhibited RKO cell proliferation and induced cell cycle arrest and apoptosis. 13-S-HODE produced similar effects in HT-29 cells. Our observations indicate that: (i) human colon cancers are associated with a down-regulation in 15-LOX-1 expression and a reduction in 13-S-HODE intracellular levels; (ii) 13-S-HODE can suppress cell proliferation and induce apoptosis in transformed colonic epithelial cells.
Abbreviations: DAB, 3,3'-diaminobenzidine; EGF, epidermal growth factor; H&E, hematoxylin and eosin; HRP, horseradish peroxidase; HUVEC, human umbilical vein endothelial cells; 12-S-HETE, 12-S-hydroxyeicosatetraenoic acid; 13-S-HODE, 13-S-hydroxyoctadecadienoic acid; 15-LOX, 15-lipoxygenase; NDGA, nordihydroguaiaretic acid; PBS, phosphate-buffered saline; NaBT, sodium butyrate; SHE, Syrian hamster embryo; TBS, Tris-buffered saline.
9 To whom correspondence should be addressed at present address: The University of Texas, M.D. Anderson Cancer Center, Department of Clinical Cancer Prevention, Box 236, 1515 Holcombe Boulevard, Houston, TX 77030, USA Email: ishureiq{at}notes.mdacc.tmc.edu
Disclosure statement: Dr Ramesh G.Reddy and Mr Stephen A.Spindler are previous employees of Oxford Biomedical Research Inc., which manufactures the 13-S-HODE kits.
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