State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, PR China.
School of Biopharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing, 211198, PR China.
Food Chem Toxicol. 2022 Nov;169:113450. doi: 10.1016/j.fct.2022.113450. Epub 2022 Oct 5.
Prostate cancer (PCa) cells exploit cellular metabolic reprogramming as their survival advantage, especially aberrant lipid signaling and metabolism. Although recent studies deemed that PCa tends to rely on lipid fuel in comparison with aerobic glycolysis, the relationship between lipid metabolism and cancer growth remains unknown. We demonstrated that wogonin, a naturally occurring mono-flavonoid, could induce apoptosis of PCa cells in vivo and in vitro. Mechanistically, 100 μM wogonin significantly increased the expression of proteins related to the fatty acid synthesis and accumulation as a result of stimulation of AKT phosphorylation and nuclear accumulation of sterol regulatory element-binding protein 1 (SREBP1). The wogonin-induced up-regulation of fatty acid synthase (FASN) promoted fatty acid synthesis and storage, while increased oxidation in mitochondria driven by carnitine palmitoyl-transferase 1A (CPT1A) resulted in the loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation, ultimately inducing apoptosis in DU145 and 22Rv1 cells. In vivo, 100 mg/kg of wogonin (i.v.) significantly repressed tumor growth without any obvious toxicity in the PCa xenograft model. In short, we proved that wogonin regulated the fatty acid metabolism and induced apoptosis by activating the AKT-SREBP1-FASN signaling network in human PCa cells, and it exhibited potent anti-tumor effects both in vivo and vitro. Thus it might be a promising candidate for the development of anti-cancer drugs.
前列腺癌（PCa）细胞利用细胞代谢重编程作为其生存优势，特别是异常的脂质信号和代谢。尽管最近的研究认为 PCa 倾向于依赖脂质燃料而不是有氧糖酵解，但脂质代谢与癌症生长之间的关系仍然未知。我们证明了，一种天然存在的单黄酮，白杨素，能够在体内和体外诱导 PCa 细胞凋亡。从机制上讲，100μM 的白杨素通过刺激 AKT 磷酸化和固醇调节元件结合蛋白 1（SREBP1）的核积累，显著增加了与脂肪酸合成和积累相关的蛋白质的表达。白杨素诱导的脂肪酸合酶（FASN）上调促进了脂肪酸的合成和储存，而肉碱棕榈酰转移酶 1A（CPT1A）驱动的线粒体氧化导致线粒体膜电位丧失和活性氧（ROS）积累，最终导致 DU145 和 22Rv1 细胞凋亡。在体内，100mg/kg 的白杨素（静脉注射）在 PCa 异种移植模型中没有明显毒性，显著抑制了肿瘤生长。总之，我们证明了白杨素通过激活 AKT-SREBP1-FASN 信号通路调节脂肪酸代谢并诱导人 PCa 细胞凋亡，并且在体内和体外均表现出强大的抗肿瘤作用。因此，它可能是开发抗癌药物的有前途的候选药物。
