背景:人参皂苷Rh2(G-Rh2),从人参根中提取的甾体化合物,在肿瘤治疗中得到了广泛的研究。然而,其在非小细胞肺癌(NSCLC)中的具体调控机制尚不清楚。丙酮酸脱氢酶激酶4(PDK4),细胞能量代谢的中央调节器,在各种恶性肿瘤中高表达。我们研究了G-Rh2对NSCLC恶性进展的影响,以及它如何调节PDK4影响肿瘤有氧糖酵解和线粒体功能。
方法:我们通过I增殖试验检测G-Rh2对NSCLC的抑制作用,体外迁移测定和流式细胞术。随后,我们通过建立裸鼠皮下肿瘤和转移模型验证了G-Rh2抑制肿瘤生长和转移的能力。进行蛋白质组学分析以分析G-Rh2的作用通路。此外,我们用海马评估糖酵解和线粒体功能,PET-CT,蛋白质印迹,和RT-qPCR。
结果:用G-Rh2处理在体外和体内均显著抑制肿瘤增殖和迁移能力。此外,G-Rh2抑制肿瘤的有氧糖酵解能力,包括葡萄糖的摄取和乳酸的产生,通过HIF1-α/PDK4途径。PDK4的过表达证明G-Rh2靶向抑制PDK4的表达,从而恢复线粒体功能,促进活性氧(ROS)的积累,诱导细胞凋亡。当与二氯乙酸钠混合时,PDK抑制剂,它补充了PDKs的抑制能力,协同作用作为解毒剂。
结论:G-Rh2可靶向下调HIF-1α的表达,导致肿瘤中糖酵解酶的表达降低和有氧糖酵解的抑制。此外,通过直接靶向线粒体PDK,它提高了线粒体氧化磷酸化和增强的ROS积累,从而促进肿瘤细胞经历正常的凋亡过程。
BACKGROUND: Ginsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (
PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated
PDK4 to influence tumor aerobic glycolysis and mitochondrial function.
METHODS: We examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR.
RESULTS: Treatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor\'s aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/
PDK4 pathway. Overexpression of
PDK4 demonstrated that G-Rh2 targeted the inhibition of
PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier.
CONCLUSIONS: G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.