Research Paper Volume 13, Issue 23 pp 25089—25105
The isoflavone puerarin exerts anti-tumor activity in pancreatic ductal adenocarcinoma by suppressing mTOR-mediated glucose metabolism
- 1 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 2 Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 3 Department of Laboratory Medicine, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou 325000, China
- 4 Department of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 5 Center for Health Assessment, Wenzhou Medical University, Wenzhou 325000, China
Received: June 14, 2021 Accepted: November 22, 2021 Published: December 4, 2021
https://doi.org/10.18632/aging.203725How to Cite
Copyright: © 2021 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Puerarin (8-(β-D-glucopyranosyl)-4′, 7-dihydroxyisoflavone), a natural flavonoid compound isolated from the traditional Chinese herb Radix puerariae, have been demonstrated 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. In this study, the tumor-suppressive effects of puerarin were determined by both in-vitro and in-vivo assays. 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. Puerarin treatment significantly repressed PCC proliferation. 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, 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. Therefore, these findings indicated that puerarin has therapeutic potential for the treatment of PDAC by suppressing glucose uptake and metabolism via Akt/mTOR activity.