Silencing Daxx increases the anti-tumor activity of a TRAIL/shRNA Bcl-xL-expressing oncolytic adenovirus through enhanced viral replication and cellular arrest.

Abstract:

:We previously showed that an increase of cellular Bcl-xL mediates acquired resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and knockdown of Bcl-xL expression greatly sensitized TRAIL-induced cytotoxicity. Here, we show that Daxx downregulation increases the anti-tumorigenic activity through enhancement of viral replication and cellular arrest with combination of TRAIL/shBcl-xL-induced apoptosis. This study was conducted to determine the effect of Daxx downregulation on the anti-tumorigenesis induced by oncolytic adenovirus arming TRAIL or TRAIL/shRNA of Bcl-xL genes. Unlike the enhanced cancer cell death induced by exogenous TRAIL or TRAIL plus shRNA of Bcl-xL, oncolytic adenovirus expressing TRAIL or TRAIL plus shRNA of Bcl-xL did not show much enhanced cancer cell death compared to oncolytic adenovirus itself. On the other hand, enhanced cytotoxic cell death and viral replication was observed after infection with oncolytic adenovirus expressing TRAIL plus shRNA of Bcl-xL and shRNA of Daxx at the same construct. Then we realized that enhanced adenoviral replication through Daxx downregulation was caused by increased adenoviral E1A protein expression and Daxx downregulation also stimulated cellular arrest through p21/p53 accumulation. Taken all together, we have shown here that Daxx downregulation should be essentially needed for the increase of anti-tumor activity through enhancement of viral replication and cellular arrest with the combination of TRAIL/shBcl-xL-induced apoptosis and oncolytic adenovirus.

journal_name

Cell Signal

journal_title

Cellular signalling

authors

Kang S,Kang D,Bakhtiar Ul Islam SM,Je S,Kim JH,Song JJ

doi

10.1016/j.cellsig.2015.02.028

subject

Has Abstract

pub_date

2015-06-01 00:00:00

pages

1214-24

issue

6

eissn

0898-6568

issn

1873-3913

pii

S0898-6568(15)00074-1

journal_volume

27

pub_type

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