PubMed:15837784 JSONTXT

{"project":"sentences","denotations":[{"id":"T1","span":{"begin":0,"end":101},"obj":"Sentence"},{"id":"T2","span":{"begin":102,"end":452},"obj":"Sentence"},{"id":"T3","span":{"begin":453,"end":495},"obj":"Sentence"},{"id":"T4","span":{"begin":496,"end":498},"obj":"Sentence"},{"id":"T5","span":{"begin":499,"end":567},"obj":"Sentence"},{"id":"T6","span":{"begin":568,"end":583},"obj":"Sentence"},{"id":"T7","span":{"begin":584,"end":882},"obj":"Sentence"},{"id":"T8","span":{"begin":883,"end":888},"obj":"Sentence"},{"id":"T9","span":{"begin":889,"end":894},"obj":"Sentence"},{"id":"T10","span":{"begin":895,"end":913},"obj":"Sentence"},{"id":"T11","span":{"begin":914,"end":1229},"obj":"Sentence"},{"id":"T12","span":{"begin":1230,"end":1512},"obj":"Sentence"},{"id":"T13","span":{"begin":1513,"end":1825},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"Glycosmos6-MAT","denotations":[{"id":"T1","span":{"begin":48,"end":56},"obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"T2","span":{"begin":231,"end":239},"obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"T3","span":{"begin":1297,"end":1305},"obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"T4","span":{"begin":1617,"end":1625},"obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"T5","span":{"begin":1809,"end":1817},"obj":"http://purl.obolibrary.org/obo/MAT_0000078"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"15837784-0#19#22#gene472","span":{"begin":19,"end":22},"obj":"gene472"},{"id":"15837784-0#48#63#diseaseC0376358","span":{"begin":48,"end":63},"obj":"diseaseC0376358"},{"id":"15837784-0#48#63#diseaseC0600139","span":{"begin":48,"end":63},"obj":"diseaseC0600139"}],"relations":[{"id":"19#22#gene47248#63#diseaseC0376358","pred":"associated_with","subj":"15837784-0#19#22#gene472","obj":"15837784-0#48#63#diseaseC0376358"},{"id":"19#22#gene47248#63#diseaseC0600139","pred":"associated_with","subj":"15837784-0#19#22#gene472","obj":"15837784-0#48#63#diseaseC0600139"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"CoMAGC","denotations":[{"id":"T1","span":{"begin":19,"end":30},"obj":"Gene"},{"id":"E2","span":{"begin":0,"end":15},"obj":"Negative_regulation"},{"id":"T2","span":{"begin":48,"end":63},"obj":"prostate cancer"}],"relations":[{"id":"R1","pred":"themeOf","subj":"T1","obj":"E2"},{"id":"R3","pred":"CGE-decreased","subj":"T1","obj":"T2"},{"id":"R4","pred":"CCS-cancerTOnormal","subj":"T1","obj":"T2"},{"id":"R5","pred":"PT-causality","subj":"T1","obj":"T2"},{"id":"R3","pred":"IGE-unidentifiable","subj":"T1","obj":"T2"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":1679,"end":1682},"obj":"gene:472"},{"id":"T1","span":{"begin":1809,"end":1824},"obj":"disease:C0376358"},{"id":"T2","span":{"begin":1679,"end":1682},"obj":"gene:472"},{"id":"T3","span":{"begin":1809,"end":1824},"obj":"disease:C0600139"},{"id":"T4","span":{"begin":1693,"end":1696},"obj":"gene:472"},{"id":"T5","span":{"begin":1809,"end":1824},"obj":"disease:C0376358"},{"id":"T6","span":{"begin":1693,"end":1696},"obj":"gene:472"},{"id":"T7","span":{"begin":1809,"end":1824},"obj":"disease:C0600139"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"},{"id":"R3","pred":"associated_with","subj":"T4","obj":"T5"},{"id":"R4","pred":"associated_with","subj":"T6","obj":"T7"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"Anatomy-MAT","denotations":[{"id":"T1","span":{"begin":48,"end":56},"obj":"Body_part"},{"id":"T2","span":{"begin":231,"end":239},"obj":"Body_part"},{"id":"T3","span":{"begin":1297,"end":1305},"obj":"Body_part"},{"id":"T4","span":{"begin":1617,"end":1625},"obj":"Body_part"},{"id":"T5","span":{"begin":1809,"end":1817},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"mat_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"A2","pred":"mat_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"A3","pred":"mat_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"A4","pred":"mat_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/MAT_0000078"},{"id":"A5","pred":"mat_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/MAT_0000078"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"mondo_disease","denotations":[{"id":"T1","span":{"begin":48,"end":63},"obj":"Disease"},{"id":"T2","span":{"begin":231,"end":246},"obj":"Disease"},{"id":"T3","span":{"begin":556,"end":562},"obj":"Disease"},{"id":"T4","span":{"begin":660,"end":681},"obj":"Disease"},{"id":"T5","span":{"begin":1274,"end":1278},"obj":"Disease"},{"id":"T6","span":{"begin":1617,"end":1632},"obj":"Disease"},{"id":"T7","span":{"begin":1809,"end":1824},"obj":"Disease"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MONDO_0008315"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/MONDO_0008315"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/MONDO_0004992"},{"id":"A4","pred":"mondo_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/MONDO_0008840"},{"id":"A5","pred":"mondo_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/MONDO_0014324"},{"id":"A6","pred":"mondo_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/MONDO_0008315"},{"id":"A7","pred":"mondo_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/MONDO_0008315"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"NCBITAXON","denotations":[{"id":"T1","span":{"begin":42,"end":47},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":225,"end":230},"obj":"OrganismTaxon"},{"id":"T3","span":{"begin":1291,"end":1296},"obj":"OrganismTaxon"},{"id":"T4","span":{"begin":1611,"end":1616},"obj":"OrganismTaxon"},{"id":"T5","span":{"begin":1803,"end":1808},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"9606"},{"id":"A2","pred":"db_id","subj":"T2","obj":"9606"},{"id":"A3","pred":"db_id","subj":"T3","obj":"9606"},{"id":"A4","pred":"db_id","subj":"T4","obj":"9606"},{"id":"A5","pred":"db_id","subj":"T5","obj":"9606"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}

{"project":"Anatomy-UBERON","denotations":[{"id":"T1","span":{"begin":48,"end":56},"obj":"Body_part"},{"id":"T2","span":{"begin":231,"end":239},"obj":"Body_part"},{"id":"T3","span":{"begin":1297,"end":1305},"obj":"Body_part"},{"id":"T4","span":{"begin":1617,"end":1625},"obj":"Body_part"},{"id":"T5","span":{"begin":1809,"end":1817},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/UBERON_0002367"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/UBERON_0002367"},{"id":"A3","pred":"uberon_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/UBERON_0002367"},{"id":"A4","pred":"uberon_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/UBERON_0002367"},{"id":"A5","pred":"uberon_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/UBERON_0002367"}],"text":"Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.\nTreatment 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."}