Institute of Biomedical Science, MacKay Medical College, New Taipei City, Taiwan.
General Education Center, University of Taipei, Taipei, Taiwan.
J Food Drug Anal. 2023 Dec 15;31(4):696-710. doi: 10.38212/2224-6614.3480.
Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with the second highest mortality rate in all cancer. Energy reprogramming is one of the hallmarks of cancer, and emerging evidence showed that targeting glycolysis is a promising strategy for HCC treatment. Cryptocaryone has been shown to display promising anti-cancer activity against numerous types of cancer. Previous study also indicated that cryptocaryone induces cytotoxicity by inhibiting glucose transport in cancer cells, but the detailed mechanism still needs to be elucidated. Therefore, this study aimed to investigate the relationship between the anti-cancer effect and glycolytic metabolism of cryptocaryone in human HCC cells. In this study, we found that cryptocaryone potently induced growth inhibition by apoptotic cell death in HCC cells. Cryptocaryone also suppressed the ATP synthesis, lactate production and glycolytic capacity of HCC cells. Mechanistic investigations showed that phosphorylation of Akt and c-Src, as well as the expression of HK1 were impeded by cryptocaryone. Moreover, cryptocaryone markedly increased the expression level of transcription factor FoxO1. Importantly, clinical database analysis confirmed the negative correlation between HK1 and FoxO1. High expression levels of HK-1 were positively correlated with poorer survival in patients with HCCs. These results suggest that cryptocaryone may promote cell apoptosis by inhibiting FoxO1-mediated aerobic glycolysis through Akt and c-Src signaling cascades in human HCC cells. This is the first study to indicate that cryptocaryone exerts anti-cancer property against human HCC cells. Cryptocaryone is a potential natural product worthy of further development into a promising candidate for HCC treatment.
肝细胞癌（HCC）是最常见的肝癌形式，其死亡率在所有癌症中排名第二。能量重编程是癌症的标志之一，新出现的证据表明，靶向糖酵解是治疗 HCC 的一种很有前途的策略。Cryptocaryone 已被证明对多种类型的癌症具有有前途的抗癌活性。先前的研究还表明，Cryptocaryone 通过抑制癌细胞中的葡萄糖转运来诱导细胞毒性，但详细的机制仍需要阐明。因此，本研究旨在探讨 Cryptocaryone 在人 HCC 细胞中的抗癌作用与糖酵解代谢之间的关系。在这项研究中，我们发现 Cryptocaryone 可强力诱导 HCC 细胞通过细胞凋亡而发生生长抑制。Cryptocaryone 还抑制了 HCC 细胞的 ATP 合成、乳酸生成和糖酵解能力。机制研究表明，Cryptocaryone 抑制了 Akt 和 c-Src 的磷酸化以及 HK1 的表达。此外，Cryptocaryone 显著增加了转录因子 FoxO1 的表达水平。重要的是，临床数据库分析证实了 HK1 和 FoxO1 之间存在负相关。HK-1 的高表达水平与 HCC 患者的生存较差呈正相关。这些结果表明，Cryptocaryone 可能通过 Akt 和 c-Src 信号级联抑制 FoxO1 介导的有氧糖酵解来促进细胞凋亡，在人 HCC 细胞中。这是第一项表明 Cryptocaryone 对人 HCC 细胞具有抗癌作用的研究。Cryptocaryone 是一种有前途的天然产物，值得进一步开发成为治疗 HCC 的候选药物。
