PMID- 12939469
OWN - NLM
STAT- MEDLINE
DCOM- 20040621
LR  - 20211203
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 2
IP  - 8
DP  - 2003 Aug
TI  - Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in 
      endometrial cancer cells.
PG  - 789-95
AB  - Rapamycin exerts its biological activity by inhibiting the kinase mammalian 
      target of rapamycin (mTOR), which regulates important cellular processes such as 
      control of cell cycle and cell size, translation initiation, and transcription. 
      The ability of rapamycin to inhibit cancer cell proliferation has led to efforts 
      to develop rapamycin and related mTOR inhibitors as anticancer agents. Some 
      investigators have hypothesized that loss of the PTEN tumor suppressor may 
      sensitize tumor cells to the antiproliferative activity of rapamycin because PTEN 
      loss leads to activation of the mTOR pathway. Because PTEN loss is frequent in 
      endometrial cancer, we have characterized the effect of rapamycin in endometrial 
      cancer cells. We show that rapamycin in the nanomolar concentration range exerts 
      a potent growth-inhibitory effect on endometrial cancer cells through induction 
      of cell cycle arrest. This effect is independent of PTEN status because 
      PTEN-positive ECC-1 cells are as sensitive to rapamycin as PTEN-null Ishikawa and 
      Hec-1B cells, suggesting that rapamycin may be effective against a broad range of 
      endometrial cancers. We also show that rapamycin rapidly inhibits telomerase 
      activity by decreasing the mRNA level of hTERT, the catalytic subunit of 
      telomerase. This implies that rapamycin leads to inhibition of hTERT gene 
      transcription. We demonstrate that rapamycin inhibits phosphorylation of 
      downstream targets of mTOR such as p70(S6K) kinase and 4E-BP1 translation 
      repressor. This work suggests that rapamycin is a potentially useful targeted 
      therapy for endometrial cancer and that loss of telomerase activity may be a good 
      surrogate biomarker for assessing antitumor activity of rapamycin.
FAU - Zhou, Chunxiao
AU  - Zhou C
AD  - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 
      University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, 
      USA.
FAU - Gehrig, Paola A
AU  - Gehrig PA
FAU - Whang, Young E
AU  - Whang YE
FAU - Boggess, John F
AU  - Boggess JF
LA  - eng
GR  - CA85772/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.7.49 (Telomerase)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/antagonists & inhibitors/therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - DNA-Binding Proteins
MH  - Endometrial Neoplasms/*drug therapy/*enzymology
MH  - Female
MH  - Humans
MH  - Protein Kinases/drug effects
MH  - RNA, Messenger/genetics/*metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Telomerase/genetics/*metabolism
EDAT- 2003/08/27 05:00
MHDA- 2004/06/24 05:00
CRDT- 2003/08/27 05:00
PHST- 2003/08/27 05:00 [pubmed]
PHST- 2004/06/24 05:00 [medline]
PHST- 2003/08/27 05:00 [entrez]
PST - ppublish
SO  - Mol Cancer Ther. 2003 Aug;2(8):789-95.