Anti-Proliferative and Pro-Apoptotic Effects of Short-Term Inhibition of Telomerase In Vivo and in Human Malignant B Cells Xenografted in Zebrafish

Abstract

Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viability via telomeres’ length-independent mechanism. Here we evaluate the anti-proliferative and pro-apoptotic effects of short-term telomerase inhibition in vivo in wild-type (wt) and tert mutant (terthu3430/hu3430; tert−/−) zebrafish embryos, and in malignant human B cells xenografted in casper zebrafish embryos. Short-term Tert inhibition by BIBR in wt embryos reduced cell proliferation, induced an accumulation of cells in S-phase and ultimately led to apoptosis associated with the activation of DNA damage response; all these effects were unrelated to telomere shortening/dysfunction. BIBR treatment showed no effects in tert−/− embryos. Xenografted untreated malignant B cells proliferated in zebrafish embryos, while BIBR pretreated cells constantly decreased and were significantly less than those in the controls from 24 to up to 72 h after xenotransplantation. Additionally, xenografted tumor cells, treated with BIBR prior- or post-transplantation, displayed a significant higher apoptotic rate compared to untreated control cells. In conclusion, our data demonstrate that short-term telomerase inhibition impairs proliferation and viability in vivo and in human malignant B cells xenografted in zebrafish, thus supporting therapeutic applications of TERT inhibitors in human malignancies.

TERT Promoter Mutations and rs2853669 Polymorphism: Useful Markers for Clinical Outcome Stratification of Patients With Oral Cavity Squamous Cell Carcinoma

“…The mechanism(s) by which high TERT expression ultimately facilitates cancer progression and constitutes a prognostic factor are not completely elucidated, and seems not be attributable only to TERT's ability to maintain telomere length. Indeed, accumulating evidence suggests that TERT may also contribute to carcinogenesis via telomere lengthindependent mechanisms, including enhancement of proliferation, resistance to apoptosis, inflammation, invasion and metastasis altogether contributing towards a more aggressive phenotype of cancer cells (10,11,(42)(43)(44)(45)(46)(47)(48)(49)(50). Therefore, it is conceivable that the -124 C>T TERT promoter mutation, inducing higher expression of TERT in the tumour, results in the increased severity of disease as we observed in our cohort of OCSCC patients.…”

Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients

“…Nonetheless, as demonstrated previously [24], we found that circulating TERT levels at T2 and ∆TERT levels were predictive of tumor response and prognostic of disease outcome. This is not surprising in light of accumulating evidence suggesting that, besides its canonical role in stabilizing telomeres, TERT may promote tumorigenesis through extra-telomeric functions, including enhancement of proliferation, resistance to apoptosis, inflammation, invasion and metastasis altogether contributing towards the higher resistance of cancer cells [36][37][38]. Therefore, endowed with these non-telomeric functions, TERT can participate in all the major characteristics of the cancer phenotype, thereby supporting its role as a potential prognostic tumor marker.…”

Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres

“…Shammas and co-workers reported that siRNA-mediated inhibition of telomerase activated both mitochondrial- and death-receptor-mediated pathways in Barrett’s adenocarcinoma SEG-1 cells [ 44 ]. In addition, Giunco et al observed that short-term inhibition of TERT by BIBR1532 in human malignant B cells xenografted in zebrafish led to apoptosis with induction of DDR [ 45 ].…”