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  • Original Article
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hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway

Oncogene volume 25, pages 4505–4514 (2006)Cite this article

A Corrigendum to this article was published on 24 January 2013

Abstract

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.

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Abbreviations

ΔΨm:

mitochondrial transmembrane potential

DAPI:

4′,6-diaminidino-2-phenylindole

DiOC6(3):

3,3′ dihexyloxacarbocyanine iodide

FITC:

fluorescein isothiocyanate

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

MMP:

mitochondrial membrane permeabilization

PI:

propidium iodide

PS:

phosphatidylserine

siRNA:

small interfering RNA

Z-VAD.fmk:

N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

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Acknowledgements

We thank Dr B Vogelstein (Baltimore, MD) for HCT116 cell lines. This work was supported by grants from French League against Cancer and European Union (RIGHT, ACTIVE p53) to GK and a BQR grant from Paris University XI to J-CS and GK.

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Author notes

  1. G Kroemer and J-C Soria: These authors share equal senior co-authorship.

Authors and Affiliations

  1. CNRS-UMR8125, Institut Gustave Roussy, Villejuif, France

    C Massard, Y Zermati, A-L Pauleau, N Larochette, D Métivier & G Kroemer

  2. Division of Cancer Medicine, Institut Gustave Roussy, Villejuif, France

    C Massard & J-C Soria

  3. Commissariat de l'Energie Atomique, DSV/DRR/LRO, Fontenay aux Roses Cedex, France

    L Sabatier & J-C Soria

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  1. C Massard
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Correspondence to G Kroemer or J-C Soria.

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Massard, C., Zermati, Y., Pauleau, AL. et al. hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene 25, 4505–4514 (2006). https://doi.org/10.1038/sj.onc.1209487

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