Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Bruceine A abrogates pancreatic cancer metastasis by suppressing PFKFB4-glycolysis-EMT axis.
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Lu Si-Nan, Dai Meng-Yu, Liu Wei, Di Di, Tao Wei-Wei, Duan Jin-Ao, Lu Cai, Zhao Ming
Аннотация
BACKGROUND: Pancreatic cancer (PC), a highly aggressive malignancy of the digestive system, creates an urgent need for innovative antimetastatic strategies. Emerging evidence positions aerobic glycolysis as a critical metabolic driver of cancer dissemination. The glycolytic gatekeeper enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is frequently overexpressed in malignancies. Bruceine A, a natural quassinoid, has previously been shown by our group to be with established antiproliferative and proapoptotic effects. However, the roles of bruceine A and PFKFB4 in inhibiting PC metastasis remain poorly understood.
OBJECTIVES: This study aimed to reveal the role and mechanisms of bruceine A in inhibiting PC metastasis. Furthermore, we sought to elucidate the function and molecular basis of PFKFB4-glycolysis-EMT axis in PC metastasis.
METHODS: Guided by phosphoproteomics, we integrated transwell assays, real-time monitoring, tumor xenograft in situ and subcutaneous transplantation mouse models to evaluate the effects of bruceine A on PC metastasis both in vitro and in vivo. We employed TGF-β-induced EMT models to explore the role of EMT in the antimetastatic effects of bruceine A. By establishing lentivirus stable overexpression and siRNA knockdown PFKFB4, we determined the effects of PFKFB4-glycolysis-EMT axis on PC metastasis both in vitro and in vivo.
RESULTS: We demonstrate that PFKFB4, a pivotal glycolytic gatekeeper, activates EMT and fuels metastatic dissemination under glycolytic activation. Furthermore, we identify PFKFB4 as a molecular nexus linking metabolic reprogramming to metastatic progression. Moreover, we establish that bruceine A exerts potent antimetastatic effects by dual targeting: suppressing PFKFB4-driven glycolytic reprogramming (evidenced by reduced glucose consumption, lactate accumulation, and extracellular acidification), and reversing TGF-β-induced EMT activation by downregulating N-cadherin, vimentin, and β-catenin.
CONCLUSIONS: These findings unveil PFKFB4-glycolysis-EMT axis as a druggable vulnerability in PC metastasis and position bruceine A as a potential first-in-class, dual-function agent that simultaneously suppresses tumor growth and dissemination through metabolic reprogramming.
OBJECTIVES: This study aimed to reveal the role and mechanisms of bruceine A in inhibiting PC metastasis. Furthermore, we sought to elucidate the function and molecular basis of PFKFB4-glycolysis-EMT axis in PC metastasis.
METHODS: Guided by phosphoproteomics, we integrated transwell assays, real-time monitoring, tumor xenograft in situ and subcutaneous transplantation mouse models to evaluate the effects of bruceine A on PC metastasis both in vitro and in vivo. We employed TGF-β-induced EMT models to explore the role of EMT in the antimetastatic effects of bruceine A. By establishing lentivirus stable overexpression and siRNA knockdown PFKFB4, we determined the effects of PFKFB4-glycolysis-EMT axis on PC metastasis both in vitro and in vivo.
RESULTS: We demonstrate that PFKFB4, a pivotal glycolytic gatekeeper, activates EMT and fuels metastatic dissemination under glycolytic activation. Furthermore, we identify PFKFB4 as a molecular nexus linking metabolic reprogramming to metastatic progression. Moreover, we establish that bruceine A exerts potent antimetastatic effects by dual targeting: suppressing PFKFB4-driven glycolytic reprogramming (evidenced by reduced glucose consumption, lactate accumulation, and extracellular acidification), and reversing TGF-β-induced EMT activation by downregulating N-cadherin, vimentin, and β-catenin.
CONCLUSIONS: These findings unveil PFKFB4-glycolysis-EMT axis as a druggable vulnerability in PC metastasis and position bruceine A as a potential first-in-class, dual-function agent that simultaneously suppresses tumor growth and dissemination through metabolic reprogramming.