Ma, Wai Kit, Scharner, Juergen, Costa, Ana SH, Jeong, Hyun Yun, Jackson, Michaela, Rigo, Frank, Bennett, C Frank, Krainer, Adrian R (September 2020) ASO-basedPKMSplice-switching Therapy Inhibits Hepatocellular Carcinoma Cell Growth. BioRxiv. (Unpublished)
Abstract
The M2 pyruvate kinase (PKM2) isoform is upregulated in most cancers and plays a crucial role in the Warburg effect, which is characterized by the preference for aerobic glycolysis for energy metabolism. PKM2 is an alternative-splice isoform of the PKM gene, and is a potential therapeutic target. Previously, we developed antisense oligonucleotides (ASOs) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform and induce apoptosis in cultured glioblastoma cells. Here, we explore the potential of ASO-based PKM splice-switching as a targeted therapy for liver cancer. We utilize a lead cEt/DNA ASO, which has a higher potency than MOE modification, to demonstrate that it induces PKM splice-switching and inhibits the growth of cultured hepatocellular-carcinoma (HCC) cells. This PKM isoform switch increases pyruvate-kinase activity and alters glucose metabolism. The lead ASO inhibits tumorigenesis in an orthotopic-xenograft HCC mouse model. Finally, a surrogate mouse-specific ASO induces Pkm splice-switching and inhibits HCC growth, without observable toxicity, in a genetic HCC mouse model.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing diseases & disorders > cancer > cancer types > liver cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Krainer lab CSHL labs > Pappin lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2 September 2020 |
| Date Deposited: | 13 Jul 2021 19:16 |
| Last Modified: | 29 Apr 2024 15:43 |
| URI: | https://repository.cshl.edu/id/eprint/40282 |
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