Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function.
Here, we investigated the role of telomerase on Bcl-2-dependent apoptosis. To this end, the 4625 Bcl-2/Bcl-xL bispecific antisense oligonucleotide and the HA14-1 Bcl-2 inhibitor were used. We found that apoptosis induced by 4625 oligonucleotide was associated with decreased Bcl-2 protein expression and telomerase activity, while HA14-1 triggered apoptosis without affecting both Bcl-2 and telomerase levels. Interestingly, HA14-1 treatment resulted in a profound change from predominantly nuclear to a predominantly cytoplasmic localization of hTERT. Downregulation of endogenous hTERT protein by RNA interference markedly increased apoptosis induced by both 4625 and HA14-1, while overexpression of wild-type hTERT blocked Bcl-2-dependent apoptosis in a p53-independent manner. Catalytically and biologically inactive hTERT mutants showed a similar behavior as the wild-type form, indicating that hTERT inhibited the 4625 and HA14-1-induced apoptosis regardless of telomerase activity and its ability to lengthening telomeres. Finally, hTERT overexpression abrogated 4625 and HA14-1-induced mitochondrial dysfunction and nuclear translocation of hTERT. In conclusion, our results demonstrate that hTERT is involved in mitochondrial apoptosis induced by targeted inhibition of Bcl-2.
Del Bufalo
D
D
Experimental Chemotherapy Laboratory, Experimental Research Center, Regina Elena Cancer Institute, Rome 00158, Italy.
Rizzo
A
A
Trisciuoglio
D
D
Cardinali
G
G
Torrisi
M R
MR
Zangemeister-Wittke
U
U
Zupi
G
G
Biroccio
A
A
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016158:Genes, p53 / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013873:Thionucleotides / Q000235:genetics / Q000494:pharmacology; D014162:Transfection
D001578:Benzopyrans; D004268:DNA-Binding Proteins; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; C408162:oblimersen; D019098:Telomerase