ASO-basedPKMSplice-switching Therapy Inhibits Hepatocellular Carcinoma Cell Growth

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 (Unpublished)

DOI: 10.1101/2020.09.01.278580


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

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving