hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway.
hTERT is the catalytic subunit of the telomerase and is hence required for telomerase maintenance activity and cancer cell immortalization. Here, we show that acute hTERT depletion has no adverse effects on the viability or proliferation of cervical and colon carcinoma cell lines, as evaluated within 72 h after transfection with hTERT-specific small interfering RNAs (siRNAs). Within the same time frame, hTERT depletion facilitated the induction of apoptotic cell death by cisplatin, etoposide, mitomycin C and reactive oxygen species, yet failed to sensitize cells to death induction via the CD95 death receptor. Experiments performed with p53 knockout cells or chemical p53 inhibitors revealed that p53 was not involved in the chemosensitizing effect of hTERT knockdown. However, the proapoptotic Bcl-2 family protein Bax was involved in cell death induction by hTERT siRNAs. Depletion of hTERT facilitated the conformational activation of Bax induced by genotoxic agents. Moreover, Bax knockout abolished the chemosensitizing effect of hTERT siRNAs. Inhibition of mitochondrial membrane permeabilization by overexpression of Bcl-2 or expression of the cytomegalovirus-encoded protein vMIA (viral mitochondrial inhibitor of apoptosis), which acts as a specific Bax inhibitor, prevented the induction of cell death by the combination of hTERT depletion and chemotherapeutic agents. Altogether, our data indicate that hTERT inhibition may constitute a promising strategy for facilitating the induction of the mitochondrial pathway of apoptosis.
Massard
C
C
CNRS-UMR8125, Institut Gustave Roussy, Villejuif, France.
Zermati
Y
Y
Pauleau
A-L
AL
Larochette
N
N
Métivier
D
D
Sabatier
L
L
Kroemer
G
G
Soria
J-C
JC
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D016685:Mitomycin / Q000494:pharmacology; D017382:Reactive Oxygen Species; D019098:Telomerase / Q000378:metabolism / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D016685:Mitomycin; D005047:Etoposide; D019098:Telomerase; D002945:Cisplatin