title: Overexpression of platelet-type 12-lipoxygenase promotes tumor cell survival by enhancing alpha(v)beta(3) and alpha(v)beta(5) integrin expression.
abstract: Arachidonic acid metabolism leads to the generation of biologically active metabolites that regulate cell growth and proliferation, as well as survival and apoptosis. We have demonstrated previously that platelet-type 12-lipoxygenase (LOX) regulates the growth and survival of a number of cancer cells. In this study, we show that overexpression of platelet-type 12-LOX in prostate cancer PC3 cells or epithelial cancer A431 cells significantly extended their survival and delayed apoptosis when cultured under serum-free conditions. These effects were shown to be a result of enhanced surface integrin expression, resulting in a more spread morphology of the cells in culture. PC3 cells transfected with 12-LOX displayed increased alpha(v)beta(3) and alpha(v)beta(5) integrin expression, whereas other integrins were unaltered. Transfected A431 cells did not express alpha(v)beta(3); however, alpha(v)beta(5) integrin expression was increased. Treatment of both transfected cell lines with monoclonal antibody to alpha(v)beta(5) (and in the case of PC3 cells, anti-alpha(v)beta(3)) resulted in significant apoptosis. In addition, treatment with 100 nM 12(S)-hydroxy-eicosatetraenoic acid, the end product of platelet-type 12-LOX, but not other hydroxy-eicosatetraenoic acids, enhanced the survival of wild-type PC3 and A431 cells and resulted in increased expression of alpha(v)beta(5). Furthermore, Baicalein or N-benzyl-N-hydroxy-5-phenylpentamide, specific 12-LOX inhibitors, significantly decreased alpha(v)beta(5)-mediated adhesion and survival in 12-LOX-overexpressing cells. The results show that 12-LOX regulates cell survival and apoptosis by affecting the expression and localization of the vitronectin receptors, alpha(v)beta(3) and alpha(v)beta(5), in two cancer cell lines.
authors.affiliation: Department of Radiation Oncology, Wayne State University, Detroit, Michigan 48202, USA.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Pidgeon
authors.forename: Keqin
authors.initials: K
authors.lastname: Tang
authors.forename: Yin Long
authors.initials: YL
authors.lastname: Cai
authors.forename: Evano
authors.initials: E
authors.lastname: Piasentin
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Honn
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis*; D016023:Integrins / Q000096:biosynthesis*; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019030:Receptors, Vitronectin / Q000096:biosynthesis*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase