Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma Lin, Jing et al. Molecular Therapy - Nucleic Acids, Volume 9, 263 - 273
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.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
This work was supported by Agency for Science, Technology and Research (A*STAR), Singapore . K.B.W. and U.S. acknowledge support from JCO-ASTAR (grant 1231BFG043 ). K.B.W. acknowledges support from an IHPC Independent Investigatorship . Z.W. acknowledges support from the National Medical Research Council (grant NMRC/TCR/007-NCC/2013 ).