Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

Oncogene. 2005 May 19;24(22):3583-95. doi: 10.1038/sj.onc.1208406.


Normal human prostatic (NHP) epithelial cells undergo senescence in vitro and in vivo, but little is known about the tissue-specific molecular mechanisms. Here we first characterize young primary NHP cells as CK5(+)/CK18(+) intermediate basal cells that also express several other putative stem/progenitor cell markers including p63, CD44, alpha2beta1, and hTERT. When cultured in serum- and androgen-free medium, NHP cells gradually lose the expression of these markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-lipoxygenase 2 (15-LOX2), a molecule with a restricted tissue expression and most abundantly expressed in adult human prostate, in the replicative senescence of NHP cells. First, the 15-LOX2 promoter activity and the mRNA and protein levels of 15-LOX2 and its multiple splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner. Second, all immortalized prostate epithelial cells and prostate cancer cells do not express 15-LOX2. Third, PCa cells stably transfected with 15-LOX2 or 15-LOX2sv-b, a splice variant that does not possess arachidonate-metabolizing activity, show a passage-related senescence-like phenotype. Fourth, infection of early-passage NHP cells with retroviral vectors encoding 15-LOX2 or 15-LOX2sv-b induces partial cell-cycle arrest and big and flat senescence-like phenotype. Finally, 15-LOX2 protein expression in human prostate correlates with age. Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Biomarkers, Tumor
  • Blotting, Western
  • Cellular Senescence / physiology*
  • Humans
  • Male
  • Middle Aged
  • Prostate / cytology*
  • Prostate / enzymology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / physiology*
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Up-Regulation


  • Biomarkers, Tumor
  • Arachidonate 15-Lipoxygenase