Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Pharmacol Res. 2021 Jul;169:105658. doi: 10.1016/j.phrs.2021.105658. Epub 2021 May 14.
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.
胰腺癌是预后最差、5 年生存率最低的恶性肿瘤之一。在本研究中，我们报告称，在体外和体内，从苦木科鸦胆子属植物 Brucea javanica（L.）Merr. 中分离得到的苦味酸 A 对人胰腺癌细胞具有很强的抗肿瘤活性。人类蛋白质组微阵列显示，6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 4（PFKFB4）是苦味酸 A 的候选靶标，荧光测量和微尺度热泳法均表明苦味酸 A 与 PFKFB4 结合。苦味酸 A 通过抑制 PFKFB4 抑制糖酵解，导致 MIA PaCa-2 细胞周期停滞和凋亡。此外，糖原合酶激酶-3β（GSK3β）被鉴定为 PFKFB4 的下游靶标和 PFKFB4 相互作用蛋白。此外，苦味酸 A 通过在胰腺癌中失调且与预后密切相关的 GSK3β 诱导细胞生长抑制和凋亡。总之，这些发现表明，苦味酸 A 通过 PFKFB4/GSK3β 介导的糖酵解抑制人胰腺癌细胞生长，它可能是治疗人类胰腺癌的有效药物。
