Document Detail


Rapamycin inhibits hTERT telomerase mRNA expression, independent of cell cycle arrest.
MedLine Citation:
PMID:  16249016     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Rapamycin and its analogues have been shown to be promising as anti-neoplastic agents but have not been extensively studied in gynecologic malignancies. Our goal was to examine the ability of rapamycin to suppress growth and regulate telomerase activity in cervical and ovarian cancer cell lines. METHODS: Cell proliferation was assessed after exposure to rapamycin. Cell cycle progression was determined by flow cytometry, and apoptosis was evaluated by DNA fragmentation. hTERT mRNA levels were quantified by real-time RT-PCR. Western blot analysis was performed to assess PTEN status, phosphorylated S6 and total S6 expression. RESULTS: Rapamycin inhibited growth of all the cervical cancer cell lines and 3 of the 4 ovarian cancer cell lines in a dose-dependent manner with IC50 values <50 nM. Loss of PTEN protein expression was seen in only one of the cervical cancer cell lines. Rapamycin induced G1 arrest in those cell lines sensitive to its growth inhibitory effects. In all cell lines, rapamycin rapidly inhibited phosphorylation of S6 and resulted in decreased levels of total S6 protein. Treatment with rapamycin reduced hTERT mRNA expression in both rapamycin-sensitive and -resistant cell lines within 24 h. Thus, the effect of rapamycin on hTERT expression was not dependent on its ability to induce G1 cell cycle arrest. CONCLUSIONS: Our data suggest that rapamycin may potentially exert its anti-tumor effects through two independent pathways by G1 cell cycle arrest as well as suppression of telomerase activity by inhibition of hTERT mRNA transcription.
Authors:
Victoria L Bae-Jump; Chunxiao Zhou; Paola A Gehrig; Young E Whang; John F Boggess
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-10-24
Journal Detail:
Title:  Gynecologic oncology     Volume:  100     ISSN:  0090-8258     ISO Abbreviation:  Gynecol. Oncol.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-02-20     Completed Date:  2006-04-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0365304     Medline TA:  Gynecol Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  487-94     Citation Subset:  IM    
Affiliation:
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7570, Chapel Hill, NC 27599, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / pharmacology*
Apoptosis / drug effects
Cell Cycle / physiology
Cell Growth Processes / drug effects
Cell Line, Tumor
DNA-Binding Proteins / antagonists & inhibitors*,  biosynthesis,  genetics
Female
Humans
Oncogene Protein v-akt / biosynthesis
Ovarian Neoplasms / drug therapy*,  enzymology,  genetics,  pathology
PTEN Phosphohydrolase / biosynthesis
Phosphorylation / drug effects
Protein Kinases / metabolism
RNA, Messenger / antagonists & inhibitors*,  biosynthesis,  genetics
Signal Transduction / drug effects
Sirolimus / pharmacology*
Telomerase / antagonists & inhibitors*,  biosynthesis,  genetics
Grant Support
ID/Acronym/Agency:
5K08CA085772/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/DNA-Binding Proteins; 0/RNA, Messenger; 53123-88-9/Sirolimus; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein; EC 2.7.11.1/Oncogene Protein v-akt; EC 2.7.7.49/Telomerase; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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