Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis

Truman, JP, Gueven, N, Lavin, M, Leibel, S, Kolesnick, R, Fuks, Z and Haimovitz-Friedman, AH (2005) Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis. Journal of Biological Chemistry, 280 24: 23262-23272. doi:10.1074/jbc.M503701200

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Author Truman, JP
Gueven, N
Lavin, M
Leibel, S
Kolesnick, R
Fuks, Z
Haimovitz-Friedman, AH
Title Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2005-01-01
Sub-type Article (original research)
DOI 10.1074/jbc.M503701200
Open Access Status File (Publisher version)
Volume 280
Issue 24
Start page 23262
End page 23272
Total pages 11
Place of publication Bethesda
Publisher Amer Soc Biochemistry Molecular Biology Inc
Language eng
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.
Keyword Biochemistry & Molecular Biology
Kinase-c Activator
Ataxia-telangiectasia
Ceramide Synthase
Ionizing-radiation
Dna-damage
Signal-transduction
Family-members
Phorbol Ester
Breast-cancer
Lncap Cells
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Wed, 17 Oct 2007, 23:39:46 EST