Growth arrest in ovarian cancer cells by hTERT inhibition short-hairpin RNA targeting human telomerase reverse transcriptase induces immediate growth inhibition but not necessarily induces apoptosis in ovarian cancer cells.
It is believed that telomerase is a terminal effector and its role is to maintain the length of telomeres. However, the main rate-limiting subunit of telomerase, human telomerase reverse transcriptase (hTERT), has been recently proved to have the ability to affect a variety of other genes such as p53 independently of the decurtation of telomere. To test whether this extra-telomeric effect could contribute to additional and immediate alterations in cellular proliferation and apoptosis, three epithelial ovarian cancer cell lines (A2780 [wild-type p53], OVCAR3 [mutant p53], and SKOV3 [p53 null]) were treated with hTERT-targeted short-hairpin RNA (shRNA), and their short-term effects were evaluated. A very fast growth inhibiting response to downregulation of hTERT was observed in all three cell lines with S-phase arrest karyotypes. But apoptosis appeared only in A2780 and OVCAR3 cells with p53 accumulation and elevated p21. In contrast, a decrease in expression of p21 was observed in SKOV3 and cell death appeared to be unaffected. These results indicated for the first time that inhibition of hTERT could induce immediate growth arrest in human ovarian carcinoma cells by blocking them in S phase, but apoptosis may only be induced via extra-telomeric effects on activation of p53 and p21.
Luo
Yi
Y
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Yi
Yongfen
Y
Yao
Zhenwei
Z
D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase