Methylthioadenosine phosphorylase, a gene frequently codeleted with p16cdkN2a/ARF, acts as a tumor suppressor in a breast cancer cell line

Scott A. Christopher, Paula Diegelman, Carl W. Porter, Warren D. Kruger

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

Abstract

The human methylthioadenosine phosphlorylase (MTAP) gene is located on 9p21 and is frequently homozygously deleted, along with p16cdkN2a/ARF, in a wide variety of human tumors and human tumor-derived cell lines. The function of MTAP is to salvage methylthioadenosine, which is produced as a byproduct of polyamine metabolism. We have reintroduced MTAP into MCF-7 breast adenocarcinoma cells and have examined its effect on the tumorigenic properties of these cells. MTAP expression does not affect the growth rate of cells in standard tissue culture conditions but severely inhibits their ability to form colonies in soft agar or collagen. In addition, MTAP-expressing cells are suppressed for tumor formation when implanted into SCID mice. This suppression of anchorage-independent growth appears to be because of the enzymatic activity of MTAP, as a protein with a missense mutation in the active site does not exhibit this phenotype. MTAP expression causes a significant decrease in intracellular polyamine levels and alters the ratio of putrescine to total polyamines. Consistent with this observation, the polyamine biosynthesis inhibitor α-difluoromethylornithine inhibits the ability of MTAP-deficient cells to form colonies in soft agar, whereas addition of the polyamine putrescine stimulates colony formation in MTAP-expressing cells. These results indicate that MTAP has tumor suppressor activity and suggest that its effects may be mediated by altering intracellular polyamine pools.

Original languageEnglish
Pages (from-to)6639-6644
Number of pages6
JournalCancer Research
Volume62
Issue number22
StatePublished - Nov 15 2002

Keywords

  • Biogenic Polyamines/metabolism
  • Breast Neoplasms/enzymology
  • Gene Deletion
  • Genes, Tumor Suppressor
  • Genes, p16
  • Humans
  • Purine-Nucleoside Phosphorylase/genetics
  • Putrescine/pharmacology
  • Transfection
  • Tumor Cells, Cultured

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