Abstract：
It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17β-estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2-silenced E2-treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC.
摘要：
已经确定丙酮酸激酶M2（PKM2）活性有助于各种癌症的代谢重编程。包括结直肠癌（CRC）。还已知雌激素或17β-雌二醇(E2)信号传导调节癌细胞中的糖酵解标志物。然而,抑制PKM2联合E2治疗是否会对CRC细胞的葡萄糖代谢产生不利影响仍有待研究。首先,我们证实了CRC细胞在不同环境条件下的代谢可塑性。接下来,我们确定了在CRC患者中上调的糖酵解标志物,并评估了E2治疗后的体外mRNA水平.我们发现PKM2表达，在CRC临床样本中高度上调，在CRC细胞中不被E2处理改变。在这项研究中,葡萄糖摄取，活性氧（ROS）的产生，乳酸生产，细胞活力，并在E2处理后评估CRC细胞的凋亡，PKM2沉默,或两者的组合。与个别治疗相比，联合治疗导致细胞活力显著降低,细胞凋亡增强.在PKM2沉默的E2处理的细胞中，葡萄糖摄取和ROS产生显着降低。本文呈现的数据表明,E2信号传导与PKM2抑制组合以负面影响CRC细胞生长的方式累积地靶向葡萄糖代谢。这些发现有望针对CRC中代谢途径改变的新型治疗策略。
