IRCCS European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy.
Nutrients. 2022 Jun 27;14(13):2669. doi: 10.3390/nu14132669.
Metabolic regulation of cancer cell growth via AMP-activated protein kinase (AMPK) activation is a widely studied strategy for cancer treatment, including leukemias. Recent notions that naturally occurring compounds might have AMPK activity led to the search for nutraceuticals with potential AMPK-stimulating activity. We found that hydroxycitric acid (HCA), a natural, safe bioactive from the plant (), has potent AMPK activity in chronic myelogenous leukemia (CML) cell line K562. HCA is a known competitive inhibitor of ATP citrate lyase (ACLY) and is widely used as a weight loss inducer. We found that HCA was able to inhibit the growth of K562 cells in in vitro and in vivo xenograft models. At the mechanistic level, we identified a direct interaction between AMPK and ACLY that seems to be sensitive to HCA treatment. Additionally, HCA treatment resulted in the co-activation of AMPK and the mammalian target of rapamycin (mTOR) pathways. Moreover, we found an enhanced unfolded protein response as observed by activation of the eIF2α/ATF4 pathway that could explain the induction of cell cycle arrest at the G2/M phase and DNA fragmentation upon HCA treatment in K562 cells. Overall, these findings suggest HCA as a nutraceutical approach for the treatment of CMLs.
通过激活 AMP 激活的蛋白激酶（AMPK）来调节癌细胞生长的代谢是治疗癌症的一种广泛研究的策略，包括白血病。最近的观点认为，天然存在的化合物可能具有 AMPK 活性，这导致了对具有潜在 AMPK 刺激活性的营养保健品的寻找。我们发现，羟基柠檬酸（HCA）是一种来自植物的天然、安全的生物活性物质（），在慢性髓性白血病（CML）细胞系 K562 中具有很强的 AMPK 活性。HCA 是三磷酸腺苷柠檬酸裂解酶（ACLY）的已知竞争性抑制剂，广泛用作减肥诱导剂。我们发现 HCA 能够抑制体外和体内异种移植模型中 K562 细胞的生长。在机制水平上，我们确定了 AMPK 和 ACLY 之间的直接相互作用，这种相互作用似乎对 HCA 治疗敏感。此外，HCA 处理导致 AMPK 和雷帕霉素（mTOR）途径的哺乳动物靶标（mTOR）途径的共激活。此外，我们发现未折叠蛋白反应增强，如 eIF2α/ATF4 途径的激活所观察到的，这可以解释在 HCA 处理 K562 细胞时诱导细胞周期停滞在 G2/M 期和 DNA 片段化。总的来说，这些发现表明 HCA 是治疗 CML 的一种营养保健品方法。
