巴基斯坦卢比
癌症研究
瓦博格效应
癌变
选择性拼接
癌症
厌氧糖酵解
基因亚型
化学
肝细胞癌
激酶
癌细胞
生物
糖酵解
分子生物学
丙酮酸激酶
基因
生物化学
新陈代谢
遗传学
作者
Wai Kit,Dillon M. Voss,Juergen Scharner,Ana S.H. Costa,Kuan-Ting Lin,Hyun Yong Jeon,John E. Wilkinson,Michaela Jackson,Frank Rigo,C. Frank Bennett,Adrian R. Krainer
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2022-03-01
卷期号:82 (5): 900-915
被引量:29
标识
DOI:10.1158/0008-5472.can-20-0948
摘要
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 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.
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