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Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung
Jing Lin1, Jia Hui Jane Lee2, Kathirvel Paramasivam3
1Bioinformatics Institute, A*STAR, 30 Biopolis Street, Singapore 138671, Singapore; Institute of High Performance Computing, A*STAR, 1 Fusionopolis Way, Singapore 138632, Singapore.
Abstract:
Self-renewing tumor-initiating cells (TICs) are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC). GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs) that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3.5-7 nM), disrupt the open reading frame (ORF) of GLDC transcript (predisposing it for nonsense-mediated decay), halt cell proliferation, and prevent colony formation in both A549 cells and TIC-enriched NSCLC tumor sphere cells (TS32). One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications.
Insights
New antisense oligonucleotides (shAONs) target glycine decarboxylase (GLDC), an enzyme overexpressed in non-small-cell lung cancer (NSCLC) tumor-initiating cells. These shAONs inhibit GLDC, halting cancer cell proliferation and reducing tumor growth, offering a potential new therapy for NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Self-renewing tumor-initiating cells (TICs) drive non-small-cell lung carcinoma (NSCLC) recurrence and chemo-resistance.
- Glycine decarboxylase (GLDC), a key metabolic enzyme, is overexpressed in TIC-enriched NSCLC and essential for tumor growth.
Purpose of the Study:
- To develop and evaluate novel therapeutic agents targeting GLDC for NSCLC treatment.
- To investigate the efficacy of splicing-modulating steric hindrance antisense oligonucleotides (shAONs) against GLDC.
Main Methods:
- Design and synthesis of shAONs to induce exon skipping and disrupt GLDC mRNA.
- In vitro testing of shAONs in A549 cells and NSCLC tumor sphere cells (TS32).
- In vivo evaluation of shAON efficacy in a mouse model of NSCLC.
Main Results:
- shAONs efficiently induced GLDC exon skipping with low IC50 values (3.5-7 nM).
- shAONs inhibited cell proliferation and colony formation in NSCLC and TIC models.
- One shAON candidate demonstrated significant tumor growth inhibition (60%) in vivo.
Conclusions:
- shAONs effectively inhibit GLDC expression in NSCLC models.
- These shAONs represent a promising therapeutic strategy for targeting GLDC in NSCLC.
