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

Jing Lin; Jia Hui Jane Lee; Kathirvel Paramasivam; Elina Pathak; Zhenxun Wang; Zacharias Aloysius Dwi Pramono; Bing Lim; Keng Boon Wee; Uttam Surana

doi:10.1016/j.omtn.2017.10.001

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

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

Authors

Jing Lin¹, Jia Hui Jane Lee², Kathirvel Paramasivam³, Elina Pathak², Zhenxun Wang², Zacharias Aloysius Dwi Pramono⁴, Bing Lim², Keng Boon Wee⁵, Uttam Surana⁶

Affiliations

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: [email protected].
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: [email protected].

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.