hTERT inhibition triggers Epstein-Barr virus lytic cycle and apoptosis in immortalized and transformed B cells: a basis for new therapies

Giunco, Silvia, Dolcetti, Riccardo, Keppel, Sonia, Celeghin, Andrea, Indraccolo, Stefano, Dal Col, Jessica, Mastorci, Katy and De Rossi, Anita (2013) hTERT inhibition triggers Epstein-Barr virus lytic cycle and apoptosis in immortalized and transformed B cells: a basis for new therapies. Clinical Cancer Research, 19 8: 2036-2047. doi:10.1158/1078-0432.CCR-12-2537


Author Giunco, Silvia
Dolcetti, Riccardo
Keppel, Sonia
Celeghin, Andrea
Indraccolo, Stefano
Dal Col, Jessica
Mastorci, Katy
De Rossi, Anita
Title hTERT inhibition triggers Epstein-Barr virus lytic cycle and apoptosis in immortalized and transformed B cells: a basis for new therapies
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2013-04-15
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-12-2537
Open Access Status Not Open Access
Volume 19
Issue 8
Start page 2036
End page 2047
Total pages 12
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Language eng
Formatted abstract
Purpose: Induction of viral lytic cycle, which induces death of host cells, may constitute a useful adjunct to current therapeutic regimens for Epstein–Barr virus (EBV)-driven malignancies. Human telomerase reverse transcriptase (hTERT), essential for the oncogenic process, may modulate the switch from latent to lytic infection. The possible therapeutic role of hTERT inhibition combined with antiviral drugs was investigated.

Experimental Design: EBV-negative BL41 and convertant EBV-positive BL41/B95.8 Burkitt's lymphoma cell lines and lymphoblastoid cell lines (LCL) were infected with retroviral vector encoding short hairpin RNA (shRNA) anti-hTERT and cultured with or without the prodrug ganciclovir. The effects on EBV lytic replication, cell proliferation, and apoptosis were characterized.

Results: hTERT silencing by shRNA induced the expression of BZLF1, EA-D, and gp350 EBV lytic proteins and triggered a complete lytic cycle. This effect was associated with downregulation of BATF, a negative regulator of BZLF1 transcription. hTERT silencing also resulted in antiproliferative and proapoptotic effects. In particular, hTERT inhibition induced an accumulation of cells in the S-phase, an effect likely due to the dephosphorylation of 4E-BP1, an AKT1-dependent substrate, which results in a decreased availability of proteins needed for cell-cycle progression. Besides inducing cell death through activation of complete EBV lytic replication, hTERT inhibition triggered AKT1/FOXO3/NOXA–dependent apoptosis in EBV-positive and -negative Burkitt's lymphoma cells. Finally, ganciclovir enhanced the apoptotic effect induced by hTERT inhibition in EBV-positive Burkitt's lymphomas and LCLs.

Conclusions: These results suggest that combination of antiviral drugs with strategies able to inhibit hTERT expression may result in therapeutically relevant effects in patients with EBV-related malignancies.
Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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