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Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL
Margherita Iaboni1, Valentina Russo1, Raffaela Fontanella2
1Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
Abstract:
TNF-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent for its remarkable ability to selectively induce apoptosis in cancer cells, without affecting the viability of healthy bystander cells. The TRAIL tumor suppressor pathway is deregulated in many human malignancies including lung cancer. In human non-small cell lung cancer (NSCLC) cells, sensitization to TRAIL therapy can be restored by increasing the expression levels of the tumor suppressor microRNA-212 (miR-212) leading to inhibition of the anti-apoptotic protein PED/PEA-15 implicated in treatment resistance. In this study, we exploited a previously described RNA aptamer inhibitor of the tyrosine kinase receptor Axl (GL21.T) expressed on lung cancer cells, as a means to deliver miR-212 into human NSCLC cells expressing Axl. We demonstrate efficient delivery of miR-212 following conjugation of the miR to GL21.T (GL21.T-miR212 chimera). We show that the chimera downregulates PED and restores TRAIL-mediate cytotoxicity in cancer cells. Importantly, treatment of Axl+ lung cancer cells with the chimera resulted in (i) an increase in caspase activation and (ii) a reduction of cell viability in combination with TRAIL therapy. In conclusion, we demonstrate that the GL21.T-miR212 chimera can be employed as an adjuvant to TRAIL therapy for the treatment of lung cancer.
Insights
This study developed a novel chimera (GL21.T-miR212) to deliver microRNA-212 (miR-212) into lung cancer cells, enhancing TRAIL therapy effectiveness against cancer by restoring apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but is often ineffective due to pathway deregulation in malignancies.
- MicroRNA-212 (miR-212) acts as a tumor suppressor in non-small cell lung cancer (NSCLC) by inhibiting the anti-apoptotic protein PED/PEA-15, restoring TRAIL sensitivity.
- The tyrosine kinase receptor Axl is overexpressed in lung cancer and can be targeted by the RNA aptamer GL21.T.
Purpose of the Study:
- To develop a targeted delivery system for miR-212 to enhance TRAIL-based cancer therapy in NSCLC.
- To investigate the efficacy of a GL21.T-miR212 chimera in restoring TRAIL-mediated cytotoxicity in Axl-expressing lung cancer cells.
Main Methods:
- Conjugation of miR-212 to the Axl-targeting aptamer GL21.T to create the GL21.T-miR212 chimera.
- Treatment of Axl-positive NSCLC cells with the chimera, alone and in combination with TRAIL therapy.
- Assessment of PED/PEA-15 downregulation, caspase activation, and cell viability.
Main Results:
- The GL21.T-miR212 chimera efficiently delivered miR-212 into Axl+ NSCLC cells.
- The chimera successfully downregulated PED/PEA-15 and restored TRAIL-induced apoptosis.
- Combined treatment with the chimera and TRAIL significantly increased caspase activation and reduced cell viability in lung cancer cells.
Conclusions:
- The GL21.T-miR212 chimera is a viable strategy for targeted miR-212 delivery in lung cancer.
- This chimera can serve as an effective adjuvant to TRAIL therapy, overcoming treatment resistance in NSCLC.
- The approach holds promise for improving the therapeutic outcomes of TRAIL-based lung cancer treatments.
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