Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis Journal Article
| Authors: | Truman, J. P.; Gueven, N.; Lavin, M.; Leibel, S.; Kolesnick, R.; Fuks, Z.; Haimovitz-Friedman, A. |
| Article Title: | Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis |
| 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. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | controlled study; human cell; promoter region; dna-binding proteins; radiation dose; flow cytometry; protein localization; cell cycle proteins; cell death; cell cycle; reverse transcription polymerase chain reaction; apoptosis; down-regulation; genetic transcription; enzyme activation; dose-response relationship, drug; enzyme activity; cell line, tumor; transfection; time factors; dose-response relationship, radiation; prostate cancer; prostatic neoplasms; rna; blotting, western; biosynthesis; dna; kinetics; reverse transcriptase polymerase chain reaction; tumors; rna, messenger; protein-serine-threonine kinases; cancer cell; tumor suppressor proteins; irradiation; transcription factor sp1; sp1 transcription factor; atm protein; radiosensitivity; down regulation; molecular biology; dna binding; oxidoreductases; biochemistry; radiation-sensitizing agents; cell separation; enzymes; ceramide; ceramides; oligonucleotides, antisense; ataxia telangiectasia; phorbol 13 acetate 12 myristate; sphingosine acyltransferase; cells; radiation-induced apoptosis; antisense oligonucleotide; sphingolipid; promoter regions (genetics); clinical applications; ceramide synthase (cs); gel shift analysis; protein kinase c activator |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 280 |
| Issue: | 24 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2005-06-17 |
| Start Page: | 23262 |
| End Page: | 23272 |
| Language: | English |
| DOI: | 10.1074/jbc.M503701200 |
| PUBMED: | 15837784 |
| PROVIDER: | scopus |
| PMCID: | PMC1855286 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 31" - "Export Date: 24 October 2012" - "CODEN: JBCHA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work