Silencing Daxx increases the anti-tumor activity of a TRAIL/shRNA Bcl-xL-expressing oncolytic adenovirus through enhanced viral replication and cellular arrest.
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.
Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Sujin
S
Kang
Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, PR China.
Dongxu
D
Kang
Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
S M
SM
Bakhtiar Ul Islam
Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
Suyeon
S
Je
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Joo-Hang
JH
Kim
Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: jjs109@yuhs.ac.
Jae J
JJ
Song
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014779:Virus Replication; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein
Bcl-xL; Daxx; Oncolytic adenovirus; TRAIL; shRNA