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Mol Ther Nucleic Acids. 2017 Dec 15;9:263-273. doi: 10.1016/j.omtn.2017.10.001. Epub 2017 Oct 7.

Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma.

Author information

1
Bioinformatics Institute, A*STAR, 30 Biopolis Street, Singapore 138671, Singapore; Institute of High Performance Computing, A*STAR, 1 Fusionopolis Way, Singapore 138632, Singapore.
2
Genome Institute of Singapore, A*STAR, 60 Biopolis Street, Singapore 138672, Singapore.
3
Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore 117660, Singapore.
4
Department of Research, National Skin Centre, 1 Mandalay Road, Singapore 308205, Singapore.
5
Bioinformatics Institute, A*STAR, 30 Biopolis Street, Singapore 138671, Singapore; Institute of High Performance Computing, A*STAR, 1 Fusionopolis Way, Singapore 138632, Singapore. Electronic address: weekb@ihpc.a-star.edu.sg.
6
Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore 117660, Singapore; Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, Singapore 138668, Singapore; Institute of Molecular and Cellular Biology, A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address: mcbucs@imcb.a-star.edu.sg.

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.

KEYWORDS:

RNA splicing; antisense oligonucleotides; exon skipping; glycine decarboxylase; lung cancer; nonsense-mediated decay; tumor-initiating cells

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