Ambinder, Richard F

Kalu, Nene

Shamay, Meir

Shirley, Courtney M

English

PubMed

Courtney M Shirley

Nene Kalu

Meir Shamay

Richard F Ambinder

Springer - Publisher Connector

POSTER PRESENTATION Open Access
Epstein-Barr virus lytic gene expression is tightly
linked to ER stress but not cytotoxicity with
bortezomib or nelfinavir
Courtney M Shirley*, Nene Kalu, Meir Shamay, Richard F Ambinder
From 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies
(ICMAOI)
Bethesda, MD, USA. 7-8 November 2011
Epstein-Barr virus (EBV) is associated with AIDS-related
lymphomas and other malignancies. We have previously
shown that the proteasome inhibitor bortezomib is an acti-
vator of EBV lytic gene expression and that these effects are
mediated by ER stress and the unfolded protein response
(UPR) [1]. We investigated the relationship between the
induction of UPR and EBV lytic gene expression with a
variety of UPR inducers, as well as the association of their
viral and antitumor effects in a variety of tumor cell lines.
Bortezomib, thapsigargin, and tunicamycin activate the
UPR and EBV lytic cycle. Recently, nelfinavir has also been
reported to lead to ER-stress and the UPR. We found a
dose-dependent relationship with bortezomib and with nel-
finavir for the induction of the UPR markers (Bip, ATF4,
XBP1s, and CHOP10), EBV lytic gene expression (mea-
sured as ZTA RNA), and cell toxicity in Burkitt’s lym-
phoma cell lines.. Blocking ER stress and UPR activation,
by cycloheximide (CHX) treatment or by Bip knockdown,
diminished ZTA induction but had no effect on cellular
toxicity. We also studied EBV lymphoblastoid cell lines
(LCLs). In contrast to the BL cell lines, bortezomib did not
induce ER stress, activate the UPR or lead to EBV lytic gene
expression but was nonetheless toxic to LCLs. These results
indicate that bortezomib and nelfinavir both induce ER
stress and UPR leading to EBV lytic reactivation in BL cells.
UPR induction corresponds with EBV lytic gene induction
but appears to be distinct from cellular toxicity. Our find-
ings suggest that ER stress, UPR and viral activation are clo-
sely linked but may be separable from the cytotoxic effects
of some pharmacologic inducers. Bortezomib and nelfinavir
may serve as laboratory and clinical tools for manipulating
viral gene expression in EBV associated malignancies.
Published: 19 April 2012
Reference
1. Shirley CM, Chen J, Shamay M, Li H, Zahnow CA, Hayward SD,
Ambinder RF: Bortezomib induction of C/EBPβ mediates Epstein-Barr
virus lytic activation in Burkitt lymphoma. Blood 2011, 117(23):6297-6303.
doi:10.1186/1750-9378-7-S1-P32
Cite this article as: Shirley et al.: Epstein-Barr virus lytic gene expression
is tightly linked to ER stress but not cytotoxicity with bortezomib or
nelfinavir. Infectious Agents and Cancer 2012 7(Suppl 1):P32.
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* Correspondence: cofarre1@jhmi.edu
Department of Oncology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
Shirley et al. Infectious Agents and Cancer 2012, 7(Suppl 1):P32
http://www.infectagentscancer.com/content/7/S1/P32
© 2012 Shirley et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.


Epstein-Barr virus lytic gene expression is tightly linked to ER stress but not cytotoxicity with bortezomib or nelfinavir

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Infectious Agents and Cancer

Shirley Courtney M

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Shamay Meir

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Ambinder RF: Bortezomib induction of C/EBPβ mediates Epstein-Barr virus lytic activation in Burkitt lymphoma. Blood

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Epstein-Barr virus lytic gene expression is tightly linked to ER stress but not cytotoxicity with bortezomib or nelfinavir

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