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Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss

Authors
 Hyun Jung Ji  ;  Sun Young Rha  ;  Hei Cheul Jeung  ;  Sang Hwa Yang  ;  Sung Whan An  ;  Hyun Cheol Chung 
Citation
 BREAST CANCER RESEARCH AND TREATMENT, Vol.93(3) : 227-236, 2005 
Journal Title
 BREAST CANCER RESEARCH AND TREATMENT 
ISSN
 0167-6806 
Issue Date
2005
MeSH
Apoptosis/drug effects* ; Breast Neoplasms/drug therapy* ; Cellular Senescence/drug effects ; Cellular Senescence/genetics ; DNA-Binding Proteins/drug effects ; DNA-Binding Proteins/metabolism ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Humans ; Reverse Transcriptase Inhibitors/pharmacology* ; Telomerase/drug effects* ; Telomerase/genetics ; Telomerase/metabolism ; Telomere/drug effects* ; Telomere/metabolism ; Telomere/ultrastructure ; Transcription Factors/drug effects ; Transcription Factors/metabolism ; Tumor Cells, Cultured ; Zidovudine/pharmacology*
Keywords
apoptosis ; hTERT ; senescence ; telomerase ; telomere
Abstract
BACKGROUND: 3'-azido-2',3'-dideoxythymidine (AZT) is phosphorylated intracellularly to 3'-azido-3'-deoxythymidine-5'-triphosphate (AZT-TP), which is incorporated into telomeric DNA, thereby blocking chain elongation. AZT is also known to inhibit reverse transcriptase, as well as other cellular enzymes including DNA polymerase gamma, thymidine kinase, and telomerase. METHODS: We induced cancer cell senescence by treating MCF-7 cells with AZT in dosages of IC10 and IC20 for an extended period (about 120 population doublings (PD)). We then investigated the sequential changes in cellular growth, expression of telomerase subunits and transcription factors (c-Myc, Mad1), telomerase activity and telomere length. RESULTS: Senescence, apoptosis, growth delay, inhibition of telomerase activity and shortening of telomere length were all observed in a dose- and time-dependent manner. After the onset of senescence, the apoptosis rate increased slowly during early PDs. In contrast to senescence, the apoptotic rate showed little change after AZT removal, while it increased suddenly and significantly in a dose-dependent manner upon the second introduction of AZT. Continuous shortening of the telomeric length was observed with AZT, and, upon re-exposure to AZT, shortening of the telomere occurred more rapidly than with first exposure. Of the telomerase subunits, telomerase reverse transcriptase (hTERT) and c-Myc were the first to show a reduction in activity after AZT treatment, followed by changes in hTER , Mad1 and hTEP-1. CONCLUSION: Cyclic treatment with AZT initially suppressed hTERT and c-Myc, followed by suppression of hTER, Mad1 and hTEP-1. Furthermore, the treatment accelerated both telomere loss and apoptosis, even when administered at a senescence-inducing dosage level.
Full Text
http://link.springer.com/article/10.1007%2Fs10549-005-5156-0
DOI
10.1007/s10549-005-5156-0
Appears in Collections:
5. Research Institutes (연구소) > Cancer Metastasis Research Center (암전이연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
An, Sung Whan(안성환)
Yang, Sang Hwa(양상화)
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
Jeung, Hei Cheul(정희철) ORCID logo https://orcid.org/0000-0003-0952-3679
Jee, Hyun Joong(지현정)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/150782
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