Department of Urology, Xuzhou No. 1 People's Hospital, the Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, 221004, PR China.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, PR China.
Cell Biochem Biophys. 2024 Sep;82(3):2373-2385. doi: 10.1007/s12013-024-01348-z. Epub 2024 Jun 14.
Prostate cancer (PCa) remains a leading cause of cancer-related incidence and mortality in men. Disruptions in amino acid (AA) metabolism contribute to the disease progression, with brucine, a glycine antagonist, exhibiting antitumor effects. This study explores the antitumor impact of brucine on PCa and investigates its mechanisms in regulating AA metabolic pathways. The study employed the PCa cell line DU-145, characterized by high sarcosine (Sar) levels, for various assays including Cell Counting Kit-8 (CCK8), wound healing, Transwell, 5-Ethynyl-2'-deoxyuridine (EDU), TdT mediated dUTP Nick End Labeling (TUNEL), flow cytometry, Western blot, and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Network pharmacological analysis determined the anticancer mechanisms of brucine. Sar levels in DU-145 cells were significantly higher than in normal prostatic epithelial cells RWPE-1. Treatment with brucine resulted in a marked decrease in cell viability, proliferation, invasion, and migration, while promoting apoptosis in a dose-dependent manner. Sar levels decreased with increasing brucine concentration. Network pharmacology analysis linked brucine's anticancer effect to the AA metabolism and glycine N-methyltransferase (GNMT) pathways. GNMT expression in prostate cancer tissues and The Cancer Genome Atlas database was significantly elevated compared to controls. Treatment with brucine led to downregulation of GNMT expression in DU-145 cells without significant effect on sarcosine dehydrogenase (SARDH). Addition of recombinant GNMT partially reversed the inhibitory effects of brucine on DU-145 cells. Treatment with brucine downregulates GNMT expression in DU-145 cells, reducing Sar accumulation and inhibiting tumor progression. These findings provide new insights into the antitumor mechanisms of brucine in PCa.
前列腺癌（PCa）仍然是男性癌症相关发病率和死亡率的主要原因。氨基酸（AA）代谢的紊乱导致疾病进展，甘氨酸拮抗剂马钱子碱具有抗肿瘤作用。本研究探讨了马钱子碱对 PCa 的抗肿瘤作用，并研究了其调节 AA 代谢途径的机制。该研究采用高肌氨酸（Sar）水平的 PCa 细胞系 DU-145 进行了各种检测，包括细胞计数试剂盒-8（CCK8）、划痕愈合、Transwell、5-乙炔基-2'-脱氧尿苷（EDU）、末端转移酶介导的 dUTP 缺口末端标记（TUNEL）、流式细胞术、Western blot 和超高效液相色谱-串联质谱（UPLC-MS/MS）。网络药理学分析确定了马钱子碱的抗癌机制。DU-145 细胞中的 Sar 水平明显高于正常前列腺上皮细胞 RWPE-1。马钱子碱处理导致细胞活力、增殖、侵袭和迁移明显下降，同时呈剂量依赖性促进细胞凋亡。随着马钱子碱浓度的增加，Sar 水平下降。网络药理学分析将马钱子碱的抗癌作用与 AA 代谢和甘氨酸 N-甲基转移酶（GNMT）途径联系起来。与对照组相比，前列腺癌组织和癌症基因组图谱数据库中的 GNMT 表达明显升高。马钱子碱处理导致 DU-145 细胞中 GNMT 表达下调，而对肌氨酸脱氢酶（SARDH）无明显影响。添加重组 GNMT 部分逆转了马钱子碱对 DU-145 细胞的抑制作用。马钱子碱下调 DU-145 细胞中的 GNMT 表达，减少 Sar 积累并抑制肿瘤进展。这些发现为马钱子碱在 PCa 中的抗肿瘤机制提供了新的见解。
