Adenovirus-TRAIL can overcome TRAIL resistance and induce a bystander effect.
TRAIL is a cytokine with a unique ability to induce apoptosis selectively in many transformed cell lines. The instability of TRAIL and the resistance of some cancer cells to TRAIL present the main obstacles for clinical experimentation. We generated an adenovirus expressing full-length TRAIL and tested its efficacy in several cancer cell lines. Ad-TRAIL-infected cancer cells localized full-length TRAIL protein to the cytoplasm and released same-sized TRAIL in the media. Ad-TRAIL was found to induce apoptotic cell death in several cancer cell lines resistant to soluble TRAIL (A549, SKOV3, HT-29 and LNCap) and in TRAIL-sensitive cell lines. Ad-TRAIL, but not soluble TRAIL, induced apoptotic cell death in TRAIL-resistant cell lines, manifested by an increased sub-G1 proportion, caspase-3 activation and PARP cleavage. Ad-TRAIL also induced a media-transferable bystander effect, but only in soluble TRAIL-sensitive cell lines. In conclusion, two novel characteristics of ad-TRAIL were found during this study. First, that ad-TRAIL can induce apoptotic cell death in several cancer cell lines resistant to sTRAIL. Second, that ad-TRAIL induces a media-transferable bystander effect, which is expected to increase its therapeutic value by allowing TRAIL to overcome the locally acting nature and low transduction rate commonly encountered in clinical situation.
Seol
Ja Young
JY
Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-744, Korea.
Park
Kyung-Ho
KH
Hwang
Chang-Il
CI
Park
Woong-Yang
WY
Yoo
Chul-Gyu
CG
Kim
Young Whan
YW
Han
Sung Koo
SK
Shim
Young-Soo
YS
Lee
Choon-Taek
CT
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D003001:Cloning, Molecular; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection / Q000379:methods*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha