Anti-proliferative and pro-apoptotic effects of short-term inhibition of telomerase in vivo and in human malignant b cells xenografted in zebrafish

Silvia Giunco, Manuela Zangrossi, Francesca Dal Pozzolo, Andrea Celeghin, Giovanni Ballin, Maria Raffaella Petrara, Aamir Amin, Francesco Argenton, Miguel Godinho Ferreira, Anita De Rossi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number2052
Pages (from-to)1-16
Number of pages16
JournalCancers
Volume12
Issue number8
DOIs
Publication statusPublished - Jul 25 2020

Keywords

  • B-cell malignancies
  • New therapeutic approach
  • TERT/telomerase
  • Xenograft
  • Zebrafish

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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