title: Convergence of eicosanoid and integrin biology: 12-lipoxygenase seeks a partner.
abstract: BACKGROUND
  Integrins and enzymes of the eicosanoid pathway are both well-established contributors to cancer. However, this is the first report of the interdependence of the two signaling systems. In a screen for proteins that interacted with, and thereby potentially regulated, the human platelet-type 12-lipoxygenase (12-LOX, ALOX12), we identified the integrin β4 (ITGB4).
  
  
  METHODS
  Using a cultured mammalian cell model, we have demonstrated that ITGB4 stimulation leads to recruitment of 12-LOX from the cytosol to the membrane where it physically interacts with the integrin to become enzymatically active to produce 12(S)-HETE, a known bioactive lipid metabolite that regulates numerous cancer phenotypes.
  
  
  RESULTS
  The net effect of the interaction was the prevention of cell death in response to starvation. Additionally, regulation of β4-mediated, EGF-stimulated invasion was shown to be dependent on 12-LOX, and downstream Erk signaling in response to ITGB4 activation also required 12-LOX.
  
  
  CONCLUSIONS
  This is the first report of an enzyme of the eicosanoid pathway being recruited to and regulated by activated β4 integrin. Integrin β4 has recently been shown to induce expansion of prostate tumor progenitors and there is a strong correlation between stage/grade of prostate cancer and 12-LOX expression. The 12-LOX enzymatic product, 12(S)-HETE, regulates angiogenesis and cell migration in many cancer types. Therefore, disruption of integrin β4-12LOX interaction could reduce the pro-inflammatory oncogenic activity of 12-LOX. This report on the consequences of 12-LOX and ITGB4 interaction sets a precedent for the linkage of integrin and eicosanoid biology through direct protein-protein association.
authors.affiliation: Department of Radiation Oncology, John D. Dingell VA Medical Center, 48201, Detroit, MI, USA. kqtang88@gmail.com.|Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. kqtang88@gmail.com.
authors.forename: Keqin
authors.initials: K
authors.lastname: Tang
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. aa9873@wayne.edu.
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. sangeetjoshi@gmail.com.|Present address: Roswell Park Cancer Institute, 14263, Buffalo, New York, USA. sangeetjoshi@gmail.com.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. etovar@med.wayne.edu.|Program in Cancer Biology, Wayne State University School of Medicine, 48202, Detroit, MI, USA. etovar@med.wayne.edu.|Present address: Van Andel Institute, 49503, Grand Rapids, MI, USA. etovar@med.wayne.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tovar
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. stucker@med.wayne.edu.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Tucker
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. maddipati@wayne.edu.
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. jcrissman@med.wayne.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Crissman
authors.affiliation: Department of Internal Medicine, University of Michigan, 48109, Ann Arbor, MI, USA. wrepaske@med.umich.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Repaskey
authors.affiliation: Department of Pathology, Bioactive Lipids Research Program, Wayne State University School of Medicine, Karmanos Cancer Institute, 431 Chemistry Building, 48202, Detroit, MI, USA. k.v.honn@wayne.edu.
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Honn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002853:Chromatography, Liquid; D006224:Cricetinae; D003412:Cricetulus; D015777:Eicosanoids / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D039663:Integrin beta4 / Q000737:chemistry / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D013058:Mass Spectrometry; D009361:Neoplasm Invasiveness; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects
chemical_list: D015777:Eicosanoids; D039663:Integrin beta4; D016859:Lipoxygenase Inhibitors; D004815:Epidermal Growth Factor; D001092:Arachidonate 12-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases