Bruceine A induces cell growth inhibition and apoptosis through PFKFB4/GSK3β signaling in pancreatic cancer

• Published in: Pharmacological research 2021-07, Vol.169, p.105658-105658, Article 105658
• Main Authors: Zhang, Pengfei, Tao, Weiwei, Lu, Cai, Fan, Lu, Jiang, Qihang, Yang, Chengbin, Shang, Erxin, Cheng, Haibo, Che, Chuntao, Duan, Jinao, Zhao, Ming
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Blotting, Western; Bruceine A; Cell Line, Tumor; Cell Proliferation - drug effects; Glycogen Synthase Kinase 3 beta - metabolism; Glycolysis; GSK3β; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Fluorescence; Neoplasm Transplantation; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; PFKFB4; Phosphofructokinase-2 - metabolism; Polymerase Chain Reaction; Quassins - pharmacology; Quassins - therapeutic use; Signal Transduction - drug effects
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2021.105658

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis and 5-year low survival rate. In the present study, we report that bruceine A, a quassinoid found in Brucea javanica (L.) Merr. has a strong antitumor activity against human pancreatic cancer cells both in vitro and in vivo. Human proteome microarray reveals that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is the candidate target of bruceine A and both fluorescence measurement and microscale thermophoresis suggest bruceine A binds to PFKFB4. Bruceine A suppresses glycolysis by inhibiting PFKFB4, leading to cell cycle arrest and apoptosis in MIA PaCa-2 cells. Furthermore, glycogen synthase kinase-3 β (GSK3β) is identified as a downstream target of PFKFB4 and an PFKFB4-interacting protein. Moreover, bruceine A induces cell growth inhibition and apoptosis through GSK3β, which is dysregulated in pancreatic cancer and closely related to the prognosis. In all, these findings suggest that bruceine A inhibits human pancreatic cancer cell growth via PFKFB4/GSK3β-mediated glycolysis, and it may serve as a potent agent for curing human pancreatic cancer. [Display omitted] •Bruceine A has a strong anti-pancreatic cancer activity both in vitro and in vivo.•PFKFB4 is a target of bruceine A.•GSK3β is a downstream signal and interacting protein of PFKFB4.•Bruceine A inhibits pancreatic cancer cell growth via PFKFB4/GSK3β signaling.