Pkm (PKM1)-KO Mouse

Pkm, which codes for pyruvate kinase muscle isoforms, is a crucial gene in the glycolytic pathway. Its alternative splicing gives rise to PKM1 and PKM2 isoforms. PKM plays a key role in the last step of aerobic glycolysis, converting phosphoenolpyruvate to pyruvate, and is thus important for energy metabolism in cells [3,4].

In hepatocellular carcinoma (HCC), antisense oligonucleotides (ASOs) that switch PKM splicing from the cancer-associated PKM2 to the PKM1 isoform inhibited tumor growth in both orthotopic HCC xenograft and genetic HCC mouse models. This PKM isoform switch increased pyruvate-kinase activity and altered glucose metabolism [1]. In a genetic HCC mouse model, a surrogate mouse-specific ASO induced Pkm splice switching and inhibited tumorigenesis without observable toxicity [1]. In colorectal cancer, the lncRNA LINC01852 inhibits SRSF5-mediated alternative splicing of PKM, decreasing the production of PKM2, which attenuates chemoresistance by inhibiting PKM2-mediated glycolysis [2].

In conclusion, Pkm is essential for glycolysis and energy metabolism. Through studies using mouse models, Pkm has been shown to play a significant role in cancer, particularly in hepatocellular and colorectal cancers. These findings suggest that targeting Pkm and its splicing mechanisms could be potential therapeutic strategies for these diseases.

References:

1. Ma, Wai Kit, Voss, Dillon M, Scharner, Juergen, Bennett, C Frank, Krainer, Adrian R. . ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth. In Cancer research, 82, 900-915. doi:10.1158/0008-5472.CAN-20-0948. https://pubmed.ncbi.nlm.nih.gov/34921016/

2. Bian, Zehua, Yang, Fan, Xu, Peiwen, Fei, Bojian, Huang, Zhaohui. 2024. LINC01852 inhibits the tumorigenesis and chemoresistance in colorectal cancer by suppressing SRSF5-mediated alternative splicing of PKM. In Molecular cancer, 23, 23. doi:10.1186/s12943-024-01939-7. https://pubmed.ncbi.nlm.nih.gov/38263157/

3. Li, Yuchao, Zhang, Shuwei, Li, Yuexian, Zang, Wenli, Pan, Yaping. 2024. The Regulatory Network of hnRNPs Underlying Regulating PKM Alternative Splicing in Tumor Progression. In Biomolecules, 14, . doi:10.3390/biom14050566. https://pubmed.ncbi.nlm.nih.gov/38785973/

4. Zahra, Kulsoom, Dey, Tulika, Mishra, Surendra Pratap, Pandey, Uma. 2020. Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis. In Frontiers in oncology, 10, 159. doi:10.3389/fonc.2020.00159. https://pubmed.ncbi.nlm.nih.gov/32195169/