title: The PTEN tumor suppressor inhibits telomerase activity in endometrial cancer cells by decreasing hTERT mRNA levels.
abstract: OBJECTIVE
  Loss of PTEN expression is one of the most prevalent and earliest molecular abnormalities associated with endometrial carcinogenesis. Given that PTEN is often absent and telomerase is overexpressed by endometrial cancers, we hypothesize that PTEN signaling is important in telomerase regulation.
  
  
  METHODS
  PTEN expression was reconstituted in the PTEN-null Ishikawa endometrial cancer cells by adenovirus-mediated gene transduction. Cell proliferation was evaluated 12-96 h after infection. Western blot analysis was performed to assess PTEN status and phosphorylated Akt expression. Telomerase activity was determined by the telomeric repeat amplification protocol (TRAP) assay. hTERT mRNA levels were assessed by real-time RT-PCR. Ishikawa cells were also treated with LY294002, a PI3-kinase inhibitor.
  
  
  RESULTS
  Infection of Ishikawa cells by replication-defective recombinant adenovirus expressing wild-type PTEN, but not control adenovirus or adenovirus expressing lipid phosphatase defective PTEN GE mutant, inhibited constitutive Akt activation and suppressed proliferation of Ishikawa cells. Infection by wild-type PTEN adenovirus, but not control adenovirus, inhibited telomerase activity 24 h after infection. This inhibition of telomerase activity was parallel to decreased hTERT mRNA levels. LY294002 treatment resulted in dose-dependent inhibition of Akt activation and cellular proliferation. LY294002 suppressed telomerase activity and decreased hTERT transcript levels in a dose-dependent manner.
  
  
  CONCLUSIONS
  Our data suggest that PTEN may regulate telomerase activity by a novel mechanism in which inhibition of Akt activation by PTEN leads to decreased hTERT mRNA levels. Thus, loss of PTEN may allow endometrial cells to continue to express high levels of telomerase activity, facilitating the neoplastic transformation of the endometrium.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, CB# 7570, Chapel Hill, NC 27599, USA.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Zhou
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
authors.forename: Young E
authors.initials: YE
authors.lastname: Whang
authors.forename: Paola A
authors.initials: PA
authors.lastname: Gehrig
authors.forename: John F
authors.initials: JF
authors.lastname: Boggess
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D048708:Cell Growth Processes; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D012333:RNA, Messenger; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051058:Oncogene Protein v-akt; D019098:Telomerase; D051059:PTEN Phosphohydrolase