Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1

Oncogene. 2003 Feb 20;22(7):1024-34. doi: 10.1038/sj.onc.1206210.


Increased expression of mac25/insulin-like growth factor binding-protein related protein-1 (IGFBP-rP1) in human breast and prostate epithelial cell lines results in the suppression of tumor growth. CDNA expression array analysis revealed increased manganese superoxide dismutase (SOD-2) expression in the mac25/IGFBP-rP1-transfected M12 human prostate cancer cell line compared to M12 control cells. SOD-2 has been postulated to be a tumor suppressor. SOD-2 was also increased in LNCaP cells stably transfected with mac25/IGFBP-rP1, but not in mac25/IGFBP-rP1-transfected PC-3 cells. Mac25 LNCaP cells had a marked decrease in tumor growth in nude mice compared to controls, but there was no difference in tumor growth in mac25 PC-3 cells compared to control. Phosphorylated Erk and Akt were increased in the M12 and LNCaP transfected mac25/IGFBP-rP1 cells but not PC-3 mac25. Inhibition of PI-3 kinase results in a marked decrease in viability of the M12-mac25 cells compared to M12 controls. Cells treated with H(2)O(2) result in an increase in phospho-ERK. Transfection of SOD-2 in M12 cells markedly decreased tumor growth, apoptosis, G1 delay in the cell cycle, and expression of senescence associated beta-galactosidase. These results suggest that one of the downstream mediators of the senescence-associated tumor suppression effect of mac25/IGFBP-rP1 is SOD-2.

Publication types

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

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology*
  • Animals
  • Apoptosis / physiology
  • Carrier Proteins / physiology*
  • Cell Line, Transformed / enzymology
  • Cell Line, Transformed / transplantation
  • Cellular Senescence
  • Chromones / pharmacology
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • G1 Phase / physiology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Insulin-Like Growth Factor Binding Proteins*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / pathology*
  • Protein Processing, Post-Translational
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / physiology*
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / physiology*
  • Transfection
  • Tumor Cells, Cultured / enzymology
  • Tumor Cells, Cultured / transplantation
  • beta-Galactosidase / biosynthesis
  • beta-Galactosidase / genetics


  • Carrier Proteins
  • Chromones
  • Enzyme Inhibitors
  • Insulin-Like Growth Factor Binding Proteins
  • Morpholines
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Recombinant Fusion Proteins
  • insulin-like growth factor binding protein-related protein 1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Mitogen-Activated Protein Kinases
  • beta-Galactosidase