Inhibition of telomerase enhances apoptosis induced by sodium butyrate via mitochondrial pathway.
Telomerase activation represents an early step in carcinogenesis. Increased telomerase activity in cervical cancer suggests a potential target for the development of novel therapeutic drugs. The aim of this study is to investigate the impact of telomerase activity on the biological features of HeLa cells and the possible mechanisms of enhanced apoptosis rate induced by sodium butyrate after telomerase inhibition. We introduced vectors encoding dominate negative (DN)-hTERT, wild-type (WT)-hTERT, or a control vector expressing only a drug-resistance marker into HeLa cells. Thus we assessed the biological effects of telomerase activity on telomere length, cell proliferation, chemosensitivity and radiosensitivity. In order to understand the mechanisms in which DN-hTERT enhances the apoptosis induced by sodium butyrate, we detected the release status of cytochrome c and apoptosis inducing factor (AIF) from mitochondria. Ectopic expression of DN-hTERT resulted in inhibition of telomerase activity, reduction of telomere length, decreased colony formation ability, and loss of tumorigenicity in nude mice. Moreover, DN-hTERT transfected HeLa cells with shortened telomeres were more susceptible to multiple chemotherapeutic agents and radiation. WT-hTERT transfected HeLa cells with longer telomeres exhibited resistance to radiation and chemotherapeutic agents. Our data demonstrate that elevated release level of cytochrome c and AIF from mitochondria might contribute to the enhanced apoptosis in DN-hTERT transfected HeLa cells after treatment with sodium butyrate. Inhibition of telomerase might serve as a promising adjunctive therapy combined with conventional therapy in cervical cancer.
Xi
L
L
Cancer Biology Research Center, TongJi Hospital, TongJi Medical School, Huazhong University of Science & Technology, Wuhan, Hubei 430030, PR China.
Chen
G
G
Zhou
J
J
Xu
G
G
Wang
S
S
Wu
P
P
Zhu
T
T
Zhang
A
A
Yang
W
W
Xu
Q
Q
Lu
Y
Y
Ma
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020148:Butyric Acid / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D019098:Telomerase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D016615:Telomere; D023041:Xenograft Model Antitumor Assays
D043823:Taxoids; D020148:Butyric Acid; D000077143:Docetaxel; D045304:Cytochromes c; D019098:Telomerase; D002945:Cisplatin