ASO-based PKM splice-switching therapy inhibits hepatocellular carcinoma growth.

Ma, Wai Kit, Voss, Dillon M, Scharner, Juergen, Costa, Ana SH, Lin, Kuang-Ting, Jeon, Hyun Yong, Wilkinson, John E, Jackson, Michaela, Rigo, Frank, Bennett, C Frank, Krainer, Adrian R (December 2021) ASO-based PKM splice-switching therapy inhibits hepatocellular carcinoma growth. Cancer Research. canres.0948.2020-canres.0948.2020. ISSN 0008-5472

URL: https://www.ncbi.nlm.nih.gov/pubmed/34921016

DOI: 10.1158/0008-5472.CAN-20-0948

Abstract

The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in regulation of the Warburg effect, which is characterized by the preference for aerobic glycolysis over oxidative phosphorylation for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene and is a potential therapeutic target. Antisense oligonucleotides (ASO) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform have been shown to induce apoptosis in cultured glioblastoma cells when delivered by lipofection. Here, we explore the potential of ASO-based PKM splice switching as a targeted therapy for liver cancer. A more potent lead cEt/DNA ASO induced PKM splice-switching and inhibited the growth of cultured hepatocellular carcinoma (HCC) cells. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism. In an orthotopic HCC xenograft mouse model, the lead ASO and a second ASO targeting a non-overlapping site inhibited tumor growth. Finally, in a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis, without observable toxicity. These results lay the groundwork for a potential ASO-based splicing therapy for HCC.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase diseases & disorders > cancer > cancer types > liver cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing diseases & disorders > viral diseases > coronavirus > therapies and treatments
CSHL Authors:	Lin, Kuan-Ting Krainer, Adrian R. Ma, Wai Kit
Communities:	CSHL labs > Krainer lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 December 2021
Date Deposited:	22 Dec 2021 15:53
Last Modified:	09 Feb 2024 19:07
PMCID:	PMC8898261
URI:	https://repository.cshl.edu/id/eprint/40463

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