Abstract
Expression of telomerase reverse transcriptase (TERT) and telomerase activity (TA) is a main feature of cancer, contributing to cell immortalization by causing telomeres dysfunction. BIBR1532 is a potent telomerase inhibitor that showed potential anti-tumor activities in several types of cancer, by triggering replicative senescence and apoptosis. In a previous work, we detected, for the first time, TERT expression and TA in preclinical models of feline oral squamous cell carcinoma (FOSCC); therefore, we aimed at extending our investigation by testing the effects of treatment with BIBR1532, in order to explore the role of telomerase in this tumor and foreshadow the possibility of it being considered as a future therapeutic target. In the present study, treatment of FOSCC cell lines SCCF1, SCCF2, and SCCF3 with BIBR1532 resulted in successful inhibition of TA, with subsequent cell growth stoppage and decrease in cell viability. Molecular data showed that up-regulation of cell cycle inhibitor p21, unbalancing of Bax/Bcl-2 ratio, and down-regulation of survival gene Survivin were mostly involved in the observed cellular events. Moreover, BIBR1532 diminished the expression of TERT and its transcriptional activator cMyc, resulting in the down-regulation of epidermal growth factor receptor (EGFR), phospho-ERK/ERK ratio, and matrix metalloproteinases (MMPs)-1/-2 and−9, likely as a consequence of an impairment of TERT extra-telomeric functions. Taken together, our data suggest that BIBR1532 exerts multiple anti-cancer activities in FOSCC by inhibiting telomerase pathway and interfering with signaling routes involved in cell proliferation, cell survival, and invasion, paving the way for future translational studies aimed at evaluating its possible employment in the treatment of this severe tumor of cats.
Highlights
Telomerase is a holoenzyme that extends telomeres, the terminal DNA sequences of chromosomes [1]
BIBR1532 blocks telomerase activity (TA) by limiting the amount of nucleotide repeats available for substrate elongation; this activity has been detected in numerous preclinical models of cancer; it has never been tested in feline oral squamous cell carcinoma (FOSCC) cell lines [10]
In SCCF1, SCCF2, and SCCF3, treatment with BIBR1532 caused the stoppage of cell growth in a dose-dependent manner, with a trend closely and correlated to the degree of enzymatic inhibition, suggesting that FOSCC cells are telomerase-addicted in their proliferative abilities
Summary
Telomerase is a holoenzyme that extends telomeres, the terminal DNA sequences of chromosomes [1]. TERT is a positive regulator of epidermal growth factor receptor (EGFR), a membrane tyrosine kinase that activates signal transduction cascades that results in cell proliferation and inhibition of apoptosis [2, 5, 6]. It modulates the expression of genes influencing cell migration and invasiveness, such as matrix metalloproteinases (MMPs)-1/-2/-9, playing a role in epithelial–mesenchymal transition and metastasis [2, 7,8,9]. TERT is considered a central regulator of the hallmarks of cancer [2]
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