Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China; Department of Pharmacy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Eur J Pharmacol. 2022 Sep 15;931:175226. doi: 10.1016/j.ejphar.2022.175226. Epub 2022 Aug 22.
Metastasis is the leading cause of death in melanoma patients. Aerobic glycolysis is a common metabolic feature in tumor and is closely related to cell growth and metastasis. Kaempferol (KAM) is one of the active ingredients in the total flavonoids of Chinese traditional medicine Sparganii Rhizoma. Studies have shown that it interferes with the cell cycle, apoptosis, angiogenesis and metastasis of tumor cells, but whether it can affect the aerobic glycolysis of melanoma is still unclear. Here, we explored the effects and mechanisms of KAM on melanoma metastasis and aerobic glycolysis. KAM inhibited the migration and invasion of A375 and B16F10 cells, and reduced the lung metastasis of melanoma cells. Extracellular acidification rates (ECAR) and glucose consumption were obviously suppressed by KAM, as well as the production of ATP, pyruvate and lactate. Mechanistically, the activity of hexokinase (HK), the first key kinase of aerobic glycolysis, was significantly inhibited by KAM. Although the total protein expression of HK2 was not significantly changed, the binding of HK2 and voltage-dependent anion channel 1 (VDAC1) on mitochondria was inhibited by KAM through AKT/GSK-3β signal pathway. In conclusion, KAM inhibits melanoma metastasis via blocking aerobic glycolysis of melanoma cells, in which the binding of HK2 and VDAC1 on mitochondria was broken.
转移是黑色素瘤患者死亡的主要原因。有氧糖酵解是肿瘤的常见代谢特征，与细胞生长和转移密切相关。山柰酚（KAM）是中药三棱总黄酮的活性成分之一。研究表明，它可以干扰肿瘤细胞的细胞周期、凋亡、血管生成和转移，但它是否能影响黑色素瘤的有氧糖酵解尚不清楚。在这里，我们探讨了 KAM 对黑色素瘤转移和有氧糖酵解的影响及其机制。KAM 抑制了 A375 和 B16F10 细胞的迁移和侵袭，并减少了黑色素瘤细胞的肺转移。KAM 明显抑制了细胞外酸化率（ECAR）和葡萄糖消耗，以及 ATP、丙酮酸和乳酸的产生。从机制上讲，KAM 显著抑制了有氧糖酵解的第一个关键激酶己糖激酶（HK）的活性。虽然 HK2 的总蛋白表达没有明显变化，但 KAM 通过 AKT/GSK-3β 信号通路抑制了 HK2 与线粒体上电压依赖性阴离子通道 1（VDAC1）的结合。总之，KAM 通过阻断黑色素瘤细胞的有氧糖酵解来抑制黑色素瘤转移，其中 HK2 与线粒体上 VDAC1 的结合被破坏。
