Death receptor signaling regulatory function for telomerase: hTERT abolishes TRAIL-induced apoptosis, independently of telomere maintenance

Abstract

Human telomerase has been implicated in cell immortalization and cancer. Recent works suggest that telomerase confers additional function required for tumorigenesis that does not depend on its ability to maintain telomeres. This new action may influence tumor therapy outcomes by yet unraveled mechanisms. Here, we show that overexpression of the catalytic subunit of telomerase (hTERT) protects a maturation-resistant acute promyelocytic leukemia (APL) cell line from apoptosis induced by the tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL) and not from apoptosis induced by chemotherapeutic drugs such as etoposide or cisplatin. Conversely, in these cells, TRAIL-induced cell death is magnified by alltrans retinoic acid (ATRA) treatment, independently of telomerase activity on telomeres. Of note, this response is subordinated neither to maturation nor to telomere shortening. This work underlines that retinoids and death receptor signaling cross-talks offer new perspectives for antitumor therapy.

Oxidative stress pathways highlighted in tumor cell immortalization: association with breast cancer outcome

“…Conversely, the absence of telomerase activity in model systems results in replicative senescence (reviewed in Ben-Porath and Weinberg, 2005), which is reversed by ectopic expression of the catalytic subunit of telomerase, hTERT (Bodnar et al, 1998). In addition to the classical role of telomerase in telomere elongation, evidence suggests that it enhances cell survival under conditions of cellular stress by regulating the expression of proliferation and apoptosis-inducing genes (Xiang et al, 2002;Zhang et al, 2003;Dudognon et al, 2004), suppresses cell differentiation (Wang et al, 2005), and contributes to the overall maintenance of chromatin and DNA-damage response (Masutomi et al, 2005). hTERT-induced immortalization of normal human mammary epithelial cells (HMEC) confers resistance to TGF-b growth inhibition (Stampfer et al, 2001), and reduction in growth factor requirements (Smith et al, 2003).…”

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

“…These diverse mechanisms of control should prove of increasing interest since telomerase is now thought to also intervene in the regulation of proliferation and apoptosis, independently of any activity in telomere length maintenance. 2,4,5 It becomes also more and more obvious that levels of telomerase expression and function can be one of the causal mechanisms that account for the therapeutic outcomes of hormone treatment or chemotherapy in cancer.…”

Separation of telomerase functions by reverse genetics

“…Transgenic mice overexpressing mTERT in keratinocytes have an increased incidence of carcinogen-induced epidermal tumors and improved wound healing (6). Ectopic telomerase expression can also confer resistance to antiproliferative and proapoptotic stimuli (18)(19)(20)(21) and enhance proliferation of diverse cell types such as mouse embryonic fibroblasts (18), cardiac myocytes (22), and human fibroblasts (23). Furthermore, hTERT can function as a RNA-dependent RNA polymerase that can bind to non-hTR RNAs, such as the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), and use them as templates to generate double-stranded RNAs that are processed into siRNAs (24).…”