title: 15-LOX-1 suppression of hypoxia-induced metastatic phenotype and HIF-1α expression in human colon cancer cells.
abstract: The expression of 15-lipoxygenase-1 (15-LOX-1) is downregulated in colon cancer and other major cancers, and 15-LOX-1 reexpression in cancer cells suppresses colonic tumorigenesis. Various lines of evidence indicate that 15-LOX-1 expression suppresses premetastatic stages of colonic tumorigenesis; nevertheless, the role of 15-LOX-1 loss of expression in cancer epithelial cells in metastases continues to be debated. Hypoxia, a common feature of the cancer microenvironment, promotes prometastatic mechanisms such as the upregulation of hypoxia-inducible factor (HIF)-1α, a transcriptional master regulator that enhances cancer cell metastatic potential, angiogenesis, and tumor cell invasion and migration. We have, therefore, tested whether restoring 15-LOX-1 in colon cancer cells affects cancer cells' hypoxia response that promotes metastasis. We found that 15-LOX-1 reexpression in HCT116, HT29LMM, and LoVo colon cancer cells inhibited survival, vascular endothelial growth factor (VEGF) expression, angiogenesis, cancer cell migration and invasion, and HIF-1α protein expression and stability under hypoxia. These findings demonstrate that 15-LOX-1 expression loss in cancer cells promotes metastasis and that therapeutically targeting ubiquitous 15-LOX-1 loss in cancer cells has the potential to suppress metastasis.
authors.affiliation: Department of Clinical Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Wu
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Zuo
authors.forename: Micheline J
authors.initials: MJ
authors.lastname: Moussalli
authors.forename: Elias
authors.initials: E
authors.lastname: Elias
authors.forename: Weiguo
authors.initials: W
authors.lastname: Xu
authors.forename: Imad
authors.initials: I
authors.lastname: Shureiqi
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D009362:Neoplasm Metastasis; D042461:Vascular Endothelial Growth Factor A
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-Lipoxygenase-1; HIF-1α; angiogenesis; hypoxia