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Bruceine A abrogates pancreatic cancer metastasis by suppressing PFKFB4-glycolysis-EMT axis
Si-Nan Lu1, Meng-Yu Dai1, Wei Liu1
1Jiangsu Provincial Key Laboratory of Functional Substances in Traditional Chinese Medicine Formulae and Innovative Drug Discovery, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resource Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China; National and Local Collaborative Engineering Center of Chinese Medicinal Resource Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing 210023, China.
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.
Insights
Bruceine A inhibits pancreatic cancer metastasis by targeting the PFKFB4-glycolysis-EMT axis. This natural compound suppresses metabolic reprogramming and reverses epithelial-mesenchymal transition, offering a dual approach to combatting tumor growth and spread.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer metastasis
Background:
- Pancreatic cancer (PC) metastasis necessitates novel antimetastatic strategies.
- Aerobic glycolysis is a key driver of cancer dissemination.
- 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is overexpressed in malignancies and linked to metastasis.
Purpose of the Study:
- To investigate the role and mechanisms of bruceine A in inhibiting PC metastasis.
- To elucidate the PFKFB4-glycolysis-EMT axis in PC metastasis.
- To explore bruceine A's potential as an antimetastatic agent.
Main Methods:
- Phosphoproteomics, transwell assays, and real-time monitoring were used.
- In vitro and in vivo models, including TGF-β-induced EMT and xenografts, were employed.
- Lentivirus-mediated overexpression and siRNA knockdown of PFKFB4 were utilized.
Main Results:
- PFKFB4 activates epithelial-mesenchymal transition (EMT) and promotes PC metastasis via glycolytic reprogramming.
- Bruceine A suppresses PFKFB4-driven glycolysis and reverses TGF-β-induced EMT.
- PFKFB4 acts as a nexus linking metabolic reprogramming to metastatic progression.
Conclusions:
- The PFKFB4-glycolysis-EMT axis represents a druggable target for PC metastasis.
- Bruceine A demonstrates potential as a first-in-class agent targeting both tumor growth and dissemination.
- Targeting metabolic reprogramming offers a novel strategy for inhibiting pancreatic cancer spread.
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