Journal
MOLECULAR CANCER THERAPEUTICS
Volume 11, Issue 11, Pages 2384-2393Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-12-0281
Keywords
-
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Association pour la Recherche contre le Cancer
- Fondation de France
- Ligue Nationale Contre le Cancer
- Federation Enfants et Sante & Societe Francaise de Lutte contre les Cancers et les Leucemies de l'Enfant et de l'Adolescent, France
Ask authors/readers for more resources
Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. Mol Cancer Ther; 11(11); 2384-93. (c) 2012 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available