Pkm (PKM2)-KO Mouse

Pkm, encoding pyruvate kinase muscle isoforms, is crucial in the glycolytic pathway. The PKM gene generates PKM1 and PKM2 through alternative splicing. PKM2 is upregulated in most cancers and is involved in the Warburg effect, where cancer cells prefer aerobic glycolysis over oxidative phosphorylation for energy metabolism [1,2,3,4,5,6,7,8].

In a genetic hepatocellular carcinoma (HCC) mouse model, a surrogate mouse-specific antisense oligonucleotide (ASO) induced Pkm splice-switching from PKM2 to PKM1. This inhibited tumorigenesis without observable toxicity, suggesting a potential ASO-based splicing therapy for HCC [1]. In colorectal cancer, the lncRNA LINC01852 inhibits SRSF5-mediated alternative splicing of PKM, decreasing PKM2 production and attenuating chemoresistance [2]. In papillary thyroid carcinoma, HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis and drive malignant progression [4]. In vascular smooth muscle cells (VSMCs), prohibitin 2 (PHB2) maintains the contractile phenotype by counteracting hnRNPA1-mediated PKM alternative splicing and glucose metabolic reprogramming [6].

In conclusion, Pkm is essential in regulating glycolysis and its alternative splicing significantly impacts cancer-related metabolic reprogramming. The use of mouse models in these studies has revealed potential therapeutic strategies for cancers like HCC and colorectal cancer, and insights into other disease-related cellular phenotypes such as in VSMCs.

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. Rong, Shikuo, Dai, Bao, Yang, Chunrong, Chen, Jian, Wu, Zeyu. 2024. HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis in papillary thyroid carcinoma and drive malignant progression. In Journal of translational medicine, 22, 914. doi:10.1186/s12967-024-05668-9. https://pubmed.ncbi.nlm.nih.gov/39380010/

5. Demeter, Jenna B, Elshaarrawi, Ahmed, Dowker-Key, Presley D, Bettaieb, Ahmed. 2022. The emerging role of PKM in keratinocyte homeostasis and pathophysiology. In The FEBS journal, 290, 2311-2319. doi:10.1111/febs.16700. https://pubmed.ncbi.nlm.nih.gov/36541050/

6. Jia, Yiting, Mao, Chenfeng, Ma, Zihan, Fu, Yi, Kong, Wei. 2022. PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing. In Circulation research, 131, 807-824. doi:10.1161/CIRCRESAHA.122.321005. https://pubmed.ncbi.nlm.nih.gov/36200440/

7. 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/

8. Voss, Dillon M, Kral, Alexander J, Sim, GeunYoung, Mishra, Lopa, Krainer, Adrian R. 2025. PKM splice-switching ASOs induce upregulation of dual-specificity phosphatases and dephosphorylation of ERK1/2 in hepatocellular carcinoma. In The Journal of biological chemistry, 301, 108345. doi:10.1016/j.jbc.2025.108345. https://pubmed.ncbi.nlm.nih.gov/39993527/