The Isoflavone Puerarin Exerts Anti-Tumor Activitiy in Pancreatic Ductal Adenocarcinoma by Suppressing Akt/mTOR Activity

Abstract Background: Puerarin (7,4’-dihydroxyisoflavone-8-β-glucopyranoside) is a natural flavonoid compound isolated from the traditional Chinese herb Radix puerariae. Recent studies have demonstrated that puerarin has potential anti-tumor effects via induction of apoptosis and inhibition of proliferation. However, the effect and molecular mechanism of puerarin in pancreatic ductal adenocarcinoma (PDAC) remains unknown.Methods: The effects of puerarin on the proliferation, apoptosis, migration and invasion of pancreatic cancer cells (PCCs), and tumor growth and metastasis in PDAC xenograft mouse model were performed. In addition, Akt/mTOR signaling activity was evaluated both in vivo and in vitro.Results: Puerarin treatment significantly repressed PCC proliferation in concentration- and time-dependent manners. Puerarin induced the mitochondrial-dependent apoptosis of PCCs by causing a Bcl-2/Bax imbalance. Moreover, puerarin inhibited PCC migration and invasion by antagonizing epithelial-mesenchymal transition (EMT). In nude mouse model, PDAC growth and metastasis were reduced by puerarin administration. Mechanistically, puerarin exerted its therapeutic effects on PDAC by suppressing Akt/mTOR signaling. Importantly, puerarin bound to the kinase domain of mTOR protein, affecting the activity of the surrounding amino acid residues associated with the binding of the ATP-Mg2+ complex. Further studies showed that the inhibitory effects of puerarin on PCCs were abolished by a mTOR activator MHY1485, indicating a crucial role of mTOR in anti-tumor effects of puerarin in PDAC. As a result, puerarin hindered glucose uptake and metabolism by downregulating the oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) dependent upon HIF-1α and glucose transporter GLUT1.Conclusion: Puerarin has therapeutic potential for the treatment of PDAC by suppressing Akt/mTOR activity.