Distinct effects of annexin A7 and p53 on arachidonate lipoxygenation in prostate cancer cells involve 5-lipoxygenase transcription

Cancer Res. 2006 Oct 1;66(19):9609-16. doi: 10.1158/0008-5472.CAN-06-1574.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Annexin A7 / physiology*
  • Arachidonate 15-Lipoxygenase / biosynthesis*
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / biosynthesis*
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonic Acids / pharmacology*
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • DNA-Binding Proteins / metabolism
  • Dexamethasone / pharmacology
  • Enzyme Induction / drug effects
  • Enzyme Induction / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, p53
  • Humans
  • Interleukin-4 / pharmacology
  • Male
  • Neoplasm Proteins / physiology*
  • Prostate / cytology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Recombinant Fusion Proteins / physiology
  • Tumor Suppressor Protein p53 / physiology*


  • Annexin A7
  • Arachidonic Acids
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • Tumor Suppressor Protein p53
  • Interleukin-4
  • Dexamethasone
  • ALOX15B protein, human
  • Arachidonate 15-Lipoxygenase
  • Arachidonate 5-Lipoxygenase