School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China; Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Research Center of Integrative Medicine, School of Basic Medical Sciences & the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China; Post-doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Biochem Pharmacol. 2019 Mar;161:149-162. doi: 10.1016/j.bcp.2019.01.016. Epub 2019 Jan 24.
Emerging evidence has suggested that targeting glycolysis may be a promising strategy for cancer treatment. Betulinic acid (BA) is a natural pentacyclic terpene that has been reported to be active in inhibiting various malignancies. Here, we showed that BA could inhibit aerobic glycolysis activity in breast cancer cell lines MCF-7 and MDA-MB-231 by hampering lactate production, glucose uptake and extracellular acidification rate (ECAR), as well as suppressing aerobic glycolysis-related proteins including c-Myc, lactate dehydrogenase A (LDH-A) and p-PDK1/PDK1 (pyruvate dehydrogenase kinase 1). Mechanistic studies validated Caveolin-1 (Cav-1) as one of key targets of BA in suppressing aerobic glycolysis, as BA administration resulted in Cav-1 upregulation, whereas silencing Cav-1 abrogated the inhibitory effect of BA on aerobic glycolysis. Further investigations demonstrated that BA suppressed aerobic glycolysis in breast cancer cells by regulating the Cav-1/NF-κB/c-Myc pathway. More meaningfully, BA significantly inhibited breast cancer growth and glycolytic activity in both the transgenic MMTV-PyVT breast cancer spontaneous model and the zebrafish breast cancer xenotransplantation model without any detectable side effects in vivo. Taken together, our study sheds novel insights into BA as a promising candidate drug for suppressing aerobic glycolysis, highlighting Cav-1 as a potential molecular target of BA and aerobic glycolysis regulation.
新出现的证据表明，靶向糖酵解可能是癌症治疗的一种有前途的策略。白桦脂酸（BA）是一种天然五环萜烯，据报道它对抑制多种恶性肿瘤具有活性。在这里，我们表明 BA 可以通过阻碍乳酸生成、葡萄糖摄取和细胞外酸化率（ECAR）来抑制乳腺癌细胞系 MCF-7 和 MDA-MB-231 的有氧糖酵解活性，同时抑制与有氧糖酵解相关的蛋白，包括 c-Myc、乳酸脱氢酶 A（LDH-A）和 p-PDK1/PDK1（丙酮酸脱氢酶激酶 1）。机制研究证实 Cav-1（Cav-1）是 BA 抑制有氧糖酵解的关键靶标之一，因为 BA 给药导致 Cav-1 上调，而沉默 Cav-1 则消除了 BA 对有氧糖酵解的抑制作用。进一步的研究表明，BA 通过调节 Cav-1/NF-κB/c-Myc 通路来抑制乳腺癌细胞的有氧糖酵解。更有意义的是，BA 显著抑制了转基因 MMTV-PyVT 乳腺癌自发模型和斑马鱼乳腺癌异种移植模型中的乳腺癌生长和糖酵解活性，而在体内没有任何可检测到的副作用。总之，我们的研究为 BA 作为抑制有氧糖酵解的有前途的候选药物提供了新的见解，强调了 Cav-1 作为 BA 和有氧糖酵解调节的潜在分子靶标。
