Human telomerase reverse transcriptase (hTERT): a target molecule for the treatment of cisplatin-resistant tumors.
BACKGROUND
Human telomerase reverse transcriptase (hTERT) is a catalytic enzyme that is required for telomerase activity (TA) and cancer progression. Telomerase inhibition or inactivation increases cellular sensitivity to UV irradiation, DNA-damaging agents, the tyrosine kinase inhibitor, imatinib, and pharmacological inhibitors, such as BIBR1532. hTERT is associated with apoptosis. Some patients show drug-resistance during anti-cancer drug treatment and the cancer cell acquire anti-apoptotic mechanism. Therefore, we attempted to study correlation between hTERT and drug-resistance.


METHODS
To study the correlation between protein level and activity of hTERT and drug-resistance, Western blotting and telomerase repeat amplification protocol (TRAP) assays were performed. To investigate whether hTERT contributes to drug resistance in tumor cells, we transiently decreased hTERT levels using small interfering RNA (siRNA) in T24/R2 cells.


RESULTS
hTERT knockdown increased Bax translocation into the mitochondria and cytochrome C release into the cytosol. Caspase inhibitors, especially Z-VAD-FMK, rescued this phenomenon, suggesting that the stability or expression of hTERT might be regulated by caspase activity.


CONCLUSIONS
These data suggest that hTERT might be a target molecule for drug-resistant tumor therapy.
Park
Yuk Pheel
YP
Medical Genomic Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Kim
Kwang Dong
KD
Kang
Seong Ho
SH
Yoon
Do Young
DY
Park
Joo Won
JW
Kim
Jong Wan
JW
Lee
Hee Gu
HG
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000628:therapy; D034741:RNA, Small Interfering; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C076615:cytochrome c''; C509186:TERT protein, human; D019098:Telomerase; D020169:Caspases; D002945:Cisplatin