title: Distinct effects of annexin A7 and p53 on arachidonate lipoxygenation in prostate cancer cells involve 5-lipoxygenase transcription.
abstract: Tumor suppressor function for Annexin A7 (ANXA7; 10q21) is based on cancer-prone phenotype in Anxa7(+/-) mouse and ANXA7 prognostic role in human cancers. Because ANXA7-caused liposome aggregation can be promoted by arachidonic acid (AA), we hypothesized that the phospholipid-binding tumor suppressor ANXA7 is associated with AA cascade. In a comparative study of ANXA7 versus canonical tumor suppressor p53 effects on AA lipoxygenation pathway in the p53-mutant and androgen-insensitive DU145 prostate cancer cells, both tumor suppressors altered gene expression of major 5-lipoxygenase (LOX) and 15-LOXs, including response to T helper 2 (Th2)-cytokine [interleukin-4 (IL-4)] and endogenous steroids (mimicked by dexamethasone). Wild-type and mutant ANXA7 distinctly affected expression of the dexamethasone-induced 15-LOX-2 (a prostate-specific endogenous tumor suppressor) as well as the IL-4-induced 15-LOX-1. On the other hand, wild-type p53 restored 5-LOX expression in DU145 to levels comparable to benign prostate epithelial cells. Using mass spectrometry of DNA affinity-enriched nuclear proteins, we detected different proteins that were bound to adjacent p53 and estrogen response elements in the 5-LOX promoter in DU145 cells introduced with ANXA7 versus p53. Sex hormone regulator 17-beta hydroxysteroid dehydrogenase 4 was identified under p53 introduction, which induced the 5-LOX expression. Meantime, nuclear proteins bound to the same 5-LOX promoter site under introduction of ANXA7 (that was associated with the repressed 5-LOX) were identified as zinc finger proteins ZNF433 and Aiolos, pyrin domain-containing NALP10, and the p53-regulating DNA repair enzyme APEX1. Thus, ANXA7 and p53 can distinctly regulate LOX transcription that is potentially relevant to the AA-mediated cell growth control in tumor suppression.
authors.affiliation: Department of Anatomy, Physiology, and Genetics, and Institute for Molecular Medicine, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Yelizaveta
authors.initials: Y
authors.lastname: Torosyan
authors.forename: Albert
authors.initials: A
authors.lastname: Dobi
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Naga
authors.forename: Katerina
authors.initials: K
authors.lastname: Mezhevaya
authors.forename: Mirta
authors.initials: M
authors.lastname: Glasman
authors.forename: Christine
authors.initials: C
authors.lastname: Norris
authors.forename: Guisen
authors.initials: G
authors.lastname: Jiang
authors.forename: Gregory
authors.initials: G
authors.lastname: Mueller
authors.forename: Harvey
authors.initials: H
authors.lastname: Pollard
authors.forename: Meera
authors.initials: M
authors.lastname: Srivastava
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D017310:Annexin A7 / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics; D001095:Arachidonic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D009363:Neoplasm Proteins / Q000502:physiology*; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D017310:Annexin A7; D001095:Arachidonic Acids; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D015847:Interleukin-4; D003907:Dexamethasone; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase