Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis Academic Article uri icon

Overview

MeSH Major

  • Apoptosis
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Down-Regulation
  • Prostatic Neoplasms
  • Protein-Serine-Threonine Kinases
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Proteins

abstract

  • Treatment with the protein kinase C activator 12-O-tetradecanoylphorbol 12-acetate (TPA) enables radiation-resistant LNCaP human prostate cancer cells to undergo radiation-induced apoptosis, mediated via activation of the enzyme ceramide synthase (CS) and de novo synthesis of the sphingolipid ceramide (Garzotto, M., Haimovitz-Friedman, A., Liao, W. C., White-Jones, M., Huryk, R., Heston, D. W. W., Cardon-Cardo, C., Kolesnick, R., and Fuks, Z. (1999) Cancer Res. 59, 5194-5201). Here, we show that TPA functions to decrease the cellular level of the ATM (ataxia telangiectasia mutated) protein, known to repress CS activation (Liao, W.-C., Haimovitz-Friedman, A., Persaud, R., McLoughlin, M., Ehleiter, D., Zhang, N., Gatei, M., Lavin, M., Kolesnick, R., and Fuks, Z. (1999) J. Biol. Chem. 274, 17908-17917). Gel shift analysis in LNCaP and CWR22-Rv1 cells demonstrated a significant reduction in DNA binding of the Sp1 transcription factor to the ATM promoter, and quantitative reverse transcription-PCR showed a 50% reduction of ATM mRNA between 8 and 16 h of TPA treatment, indicating that TPA inhibits ATM transcription. Furthermore, treatment of LNCaP, CWR22-Rv1, PC-3, and DU-145 human prostate cells with antisense-ATM oligonucleotides, which markedly reduced cellular ATM levels, significantly enhanced radiation-induced CS activation and apoptosis, leading to apoptosis at doses as a low as 1 gray. These data suggest that the CS pathway initiates a generic mode of radiation-induced apoptosis in human prostate cancer cells, regulated by a suppressive function of ATM, and that ATM might represent a potential target for pharmacologic inactivation with potential clinical applications in human prostate cancer.

publication date

  • June 17, 2005

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1855286

Digital Object Identifier (DOI)

  • 10.1074/jbc.M503701200

PubMed ID

  • 15837784

Additional Document Info

start page

  • 23262

end page

  • 72

volume

  • 280

number

  • 24