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

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 hTERTspecific 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.

The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential

“…The bars in a-c represent standard errors with ** and *** indicating Pr0.01 and Pr0.001, respectively cell death induced by mitomycin C, a potent DNA crosslinker used in cancer treatment to induce mitochondrial apoptosis. 20,21 Figure 1b shows that DN-Aven 180-362 and the bona fide apoptosis inhibitor Bcl-x L both significantly inhibited apoptosis caused by mitomycin C at different concentrations, whereas expression of full-length Aven did not confer protection under this experimental paradigm.…”

Actions of human telomerase beyond telomeres

“…In addition, it has been shown that overexpression of hTERT suppresses apoptosis at a premitochondrial step before the release of cytochrome c and apoptosis-inducing factor [32]. Recent studies showed that down-regulation of hTERT expression by hTERT specific interfering RNA (siRNA) sensitizes mitochondrial pathways of apoptosis without apparent involvement of telomere erosion due to telomerase inhibition, rather by post-translational activation of Bax protein which triggers a CD-90 independent mitochondrial pathway of apoptosis [33]. More recent report indicated that TERT promotes cellular and organismal survival independent of telomerase activity [34].…”

Inhibition of Human Tumor Cell Proliferation by the Telomerase Inhibitor TELIN

“…It is unlikely that rapid telomere shortening occurred in that cells, and high dose of TELIN may invoke another physiological response of MOLT-4 cells. hTERT is reported to function in mitochondria to suppress the course of apoptosis process, and so is expected as anticancer target (Massard et al 2006), and we have not excluded the possibility that TELIN potentially targets hTERT in mitochondoria.…”