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Adenovirus-TRAIL can overcome TRAIL resistance and induce a bystander effect
Ja Young Seol1, Kyung-Ho Park, Chang-Il Hwang
1Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-744, Korea.
Abstract:
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.
Insights
This study developed an adenovirus expressing Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) to overcome cancer cell resistance. Ad-TRAIL effectively induced apoptosis in resistant cancer cells, showing therapeutic potential.
Area of Science:
- Molecular Biology
- Cancer Research
- Virology
Background:
- Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) selectively induces apoptosis in cancer cells.
- TRAIL instability and cancer cell resistance limit its clinical application.
Purpose of the Study:
- To develop an adenovirus expressing full-length TRAIL (Ad-TRAIL) to enhance its therapeutic efficacy.
- To evaluate Ad-TRAIL's ability to induce apoptosis in TRAIL-resistant cancer cell lines.
Main Methods:
- Adenovirus vector construction expressing full-length TRAIL.
- In vitro efficacy testing of Ad-TRAIL in various human cancer cell lines.
- Assessment of apoptosis induction via sub-G1 cell cycle analysis, caspase-3 activation, and PARP cleavage.
Main Results:
- Ad-TRAIL expression led to cytoplasmic localization and media release of functional TRAIL.
- Ad-TRAIL induced apoptosis in both TRAIL-sensitive and TRAIL-resistant cancer cell lines.
- Ad-TRAIL demonstrated a media-transferable bystander effect in TRAIL-sensitive cells.
Conclusions:
- Ad-TRAIL effectively induces apoptosis in cancer cells resistant to soluble TRAIL.
- Ad-TRAIL exhibits a bystander effect, potentially increasing its therapeutic value in clinical settings.
- Ad-TRAIL offers a promising strategy to overcome limitations of soluble TRAIL in cancer therapy.