ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth.

Autor:	Ma WK; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Stratome Capital Management LP, New York, New York., Voss DM; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Stony Brook University, Stony Brook, New York., Scharner J; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Stoke Therapeutics, Bedford, Massachusetts., Costa ASH; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Icahn School of Medicine at Mount Sinai, New York, New York., Lin KT; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Skyhawk Therapeutics, Waltham, Massachusetts., Jeon HY; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Stoke Therapeutics, Bedford, Massachusetts., Wilkinson JE; University of Michigan Medical School, Ann Arbor, Michigan., Jackson M; Ionis Pharmaceuticals, Carlsbad, California., Rigo F; Ionis Pharmaceuticals, Carlsbad, California., Bennett CF; Ionis Pharmaceuticals, Carlsbad, California., Krainer AR; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Mar 01; Vol. 82 (5), pp. 900-915.
DOI:	10.1158/0008-5472.CAN-20-0948
Abstrakt:	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 constrained-ethyl (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 nonoverlapping 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. Significance: Antisense oligonucleotides are used to induce a change in PKM isoform usage in hepatocellular carcinoma, reversing the Warburg effect and inhibiting tumorigenesis. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu