Ma Liang, Zhang Xue, Liu Yan, Jin Hui, Li Dan, Zhang Hui, Feng Li, Zuo Jing, Wang Yudong, Liu Jiayin, Han Jing
Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Transl Cancer Res. 2024 Jul 31;13(7):3522-3535. doi: 10.21037/tcr-24-154. Epub 2024 Jul 11.
Despite evidence suggesting a significant role of pyruvate kinase muscle isozyme (PKM) in cancer development, its particular function in colorectal cancer (CRC) remains unclear. This study aimed to elucidate the specific role and mechanism of PKM and its isoforms, PKM1 and PKM2, in the progression of CRC.
We analyzed PKM, PKM1, and PKM2 expression in CRC tissues and their correlation with clinicopathological features. Plasmids were constructed to modulate these isoforms' expression in CRC cells. Cellular behavior changes, including glucose metabolism alterations, were assessed using the Seahorse Energy Meter, and the Cell Counting Kit-8 (CCK8) assay to determine the inhibitory concentration of 5-fluorouracil (5-FU) on different CRC cell groups.
Our results showed significant PKM overexpression in CRC tissues, which was correlated with negative prognostic factors such as advanced T stages and lymph node metastasis. A lower ratio was associated with these adverse outcomes. Functionally, overexpression decreased cell migration and invasion, increasing 5-FU sensitivity. Conversely, overexpression promoted malignant traits and reduced 5-FU sensitivity. Intriguingly, the introduction of glycolysis inhibitors attenuated the impact of on the biological functions of CRC cells, suggesting a glycolysis-dependent mechanism.
This study establishes the ratio as crucial in CRC progression and 5-FU response. PKM1 overexpression reduces CRC malignancy and increases 5-FU sensitivity, while does the opposite. Notably, glycolysis inhibitors lessen 's impact on CRC cells, highlighting a glycolysis-dependent mechanism. These insights suggest targeting isoforms and glycolysis pathways as a promising CRC therapeutic strategy, potentially enhancing treatment efficacy.
尽管有证据表明丙酮酸激酶肌肉同工酶（PKM）在癌症发展中起重要作用，但其在结直肠癌（CRC）中的具体功能仍不清楚。本研究旨在阐明PKM及其同工型PKM1和PKM2在CRC进展中的具体作用和机制。
我们分析了CRC组织中PKM、PKM1和PKM2的表达及其与临床病理特征的相关性。构建质粒以调节CRC细胞中这些同工型的表达。使用海马能量代谢分析仪和细胞计数试剂盒-8（CCK8）测定法评估细胞行为变化，包括葡萄糖代谢改变，以确定5-氟尿嘧啶（5-FU）对不同CRC细胞组的抑制浓度。
我们的结果显示CRC组织中PKM显著过表达，这与晚期T分期和淋巴结转移等不良预后因素相关。较低的[PKM2/PKM1]比值与这些不良结果相关。在功能上，PKM1过表达减少细胞迁移和侵袭，增加对5-FU的敏感性。相反，PKM2过表达促进恶性特征并降低对5-FU的敏感性。有趣的是，引入糖酵解抑制剂减弱了PKM2对CRC细胞生物学功能的影响，提示存在糖酵解依赖性机制。
本研究确定[PKM2/PKM1]比值在CRC进展和对5-FU反应中至关重要。PKM1过表达降低CRC恶性程度并增加对5-FU的敏感性，而PKM2则相反。值得注意的是，糖酵解抑制剂减轻了PKM2对CRC细胞的影响，突出了糖酵解依赖性机制。这些见解表明靶向PKM同工型和糖酵解途径是一种有前景的CRC治疗策略，可能提高治疗效果。
