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Identification of ISZ-sTRAIL Protein as a Potent Anticancer Agent for EML4-ALK-Positive Non-Small-Cell Lung Cancer
Junfeng Hu1, Junhui Guo1, Tian Qin1
1Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243002, China.
Abstract:
EML4-ALK-positive lung cancer represents an important molecular subtype of non-small-cell lung cancer (NSCLC) that initially responds to ALK inhibitors but invariably develops resistance, highlighting the need for novel targeted therapeutic strategies. Death receptors DR4 and DR5 are frequently upregulated in malignancies and can selectively induce tumor cell apoptosis upon binding TRAIL. ISZ-sTRAIL, a trimer-stabilized soluble TRAIL fusion protein, exhibits potent antitumor effects via DR4/DR5 signaling activation. However, the expression status of DR4/DR5 in EML4-ALK-positive NSCLC cells and the therapeutic potential of targeting this pathway remain poorly defined. In this study, we evaluated DR4/DR5 protein expression in EML4-ALK-positive NSCLC cells and investigated the antitumor effect of ISZ-sTRAIL produced in an Escherichia coli expression system. Our results showed that DR4 and DR5 were abundantly expressed in EML4-ALK-positive NCI-H2228 and NCI-H3122 cells compared with normal human bronchial epithelial 16HBE cells. Furthermore, ISZ-sTRAIL significantly suppressed the proliferation of NCI-H2228 and NCI-H3122 cells, with IC50 values of 4.51 ± 0.22 nM and 14.98 ± 3.34 nM, respectively, while showing low cytotoxicity toward normal 16HBE cells (IC50 > 1 μM). Moreover, ISZ-sTRAIL induced caspase-dependent apoptosis in both cell lines via activation of extrinsic and intrinsic pathway, and these effects were markedly abrogated by the pan-caspase inhibitor Z-VAD. These findings identify DR4/DR5 as a potential therapeutic target and provide preclinical evidence for the development of TRAIL-based strategies in the treatment of EML4-ALK-positive NSCLC.
Insights
Death receptors DR4 and DR5 are highly expressed in EML4-ALK-positive non-small-cell lung cancer (NSCLC). ISZ-sTRAIL effectively targets these receptors, inducing apoptosis and suppressing tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- EML4-ALK-positive non-small-cell lung cancer (NSCLC) develops resistance to ALK inhibitors, necessitating new therapies.
- Death receptors 4 and 5 (DR4/DR5) are upregulated in cancers and can trigger apoptosis via TRAIL binding.
- The role of DR4/DR5 and TRAIL-based therapies in EML4-ALK-positive NSCLC is not well understood.
Purpose of the Study:
- To assess DR4/DR5 expression in EML4-ALK-positive NSCLC cells.
- To investigate the antitumor efficacy of ISZ-sTRAIL targeting the DR4/DR5 pathway.
- To provide preclinical evidence for novel therapeutic strategies.
Main Methods:
- Evaluated DR4/DR5 protein expression in EML4-ALK-positive NSCLC cell lines (NCI-H2228, NCI-H3122) and normal bronchial epithelial cells (16HBE).
- Assessed the antitumor effects of ISZ-sTRAIL on NSCLC cell proliferation and cytotoxicity.
- Investigated ISZ-sTRAIL-induced apoptosis via caspase activation and pathway analysis.
Main Results:
- DR4 and DR5 were highly expressed in EML4-ALK-positive NSCLC cells compared to normal cells.
- ISZ-sTRAIL significantly inhibited NSCLC cell proliferation with low IC50 values (4.51 nM and 14.98 nM) and minimal toxicity to normal cells.
- ISZ-sTRAIL induced caspase-dependent apoptosis through extrinsic and intrinsic pathways, confirmed by Z-VAD inhibition.
Conclusions:
- DR4/DR5 are potential therapeutic targets in EML4-ALK-positive NSCLC.
- ISZ-sTRAIL demonstrates significant preclinical antitumor activity against this NSCLC subtype.
- TRAIL-based strategies show promise for treating EML4-ALK-positive NSCLC.
