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

Citation

Truman, J-P and Gueven, N and Lavin, M and Leibel, S and Kolesnick, R and Fuks, Z and Haimovitz-Friedman, A, Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis, Journal of Biological Chemistry, 280, (24) pp. 23262-23272. ISSN 0021-9258 (2005) [Refereed Article]


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Copyright Statement

Copyright 2005 The American Society for Biochemistry and Molecular Biology, Inc.

DOI: doi:10.1074/jbc.M503701200

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.

Item Details

Item Type:Refereed Article
Keywords:ATM, radiation-induced apoptosis, prostate cancer
Research Division:Technology
Research Group:Medical Biotechnology
Research Field:Gene and Molecular Therapy
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Medical and Health Sciences
Author:Gueven, N (Dr Nuri Guven)
ID Code:79498
Year Published:2005
Web of Science® Times Cited:43
Deposited By:Pharmacy
Deposited On:2012-09-17
Last Modified:2016-10-19
Downloads:0

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