Research Paper Volume 13, Issue 14 pp 18545—18563
The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation
- 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 The Sixth People’s Hospital of Wenzhou City, Wenzhou 325000, China
- 3 Engineering Research Center of Clinical Functional Materials and Diagnosis and Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy Sciences, Wenzhou 325000, China
- 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361000, China
- 5 Platform for Radiation Protection and Emergency Preparedness, School of Public Health and Management, Wenzhou Medical University, Wenzhou 325000, China
- 6 Center for Health Assessment, Wenzhou Medical University, Wenzhou 325000, China
- 7 Department for Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
Received: May 31, 2021 Accepted: June 1, 2021 Published: July 28, 2021
https://doi.org/10.18632/aging.203301How to Cite
Copyright: © 2021 Guo 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
Fraxetin, a natural product isolated and purified from the bark of Fraxinus bungeana A.DC., has anti-inflammatory, analgesic, and anti-dysenteric activities. This study aimed to investigate the anti-tumor effects of fraxetin in pancreatic ductal adenocarcinoma (PDA). The effects of fraxetin on the malignant biological behavior of PDA were evaluated. Besides, the effects of fraxetin on the sensitivity of PCCs to gemcitabine, angiogenesis, the epithelial-mesenchymal transition (EMT), glucose metabolism, reactive oxygen species (ROS), and STAT3 activity were analyzed. By reversing the EMT, fraxetin suppressed proliferation, invasion, and migration, and induced mitochondrial-dependent apoptosis in PCCs. Also, treatment with fraxetin inhibited PDA growth and metastasis in nude mouse models. Furthermore, fraxetin made PCCs more sensitive to the chemotherapy drug gemcitabine. Mechanically, fraxetin treatment suppressed oncogenic KRAS-triggered STAT3 activation in PCCs and PDA tissues. Fraxetin shows significant interactions with STAT3 Src Homology 2 (SH2) domain residues, thereby preventing its homo-dimer formation, which then blocks the activation of downstream signal pathways. The anti-tumor activity of fraxetin in PDA was functionally rescued by a STAT3 activator colivelin. As a result, fraxetin hindered hypoxia-induced angiogenesis by decreasing HIF-1α and VEGFA expression, controlled glucose metabolism by reducing GLUT1 expression, inhibited the EMT by blocking the Slug-E-cadherin axis, and drove ROS-mediated apoptosis by regulating the STAT3-Ref1 axis. In conclusion, fraxetin enhances the anti-tumor activity of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.
Abbreviations
2-DG: 2-Deoxyglucose 2-Deoxyglucose; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; CCK-8: cell counting kit 8; DAPI: ’’4’6-diamidino-2-phenylindole; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; FCCP: Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GLUT1: glucose transporter type 1; HIF-1α: hypoxia-inducible factor-1α; JAK2: Janus kinase 2; ROS: reactive oxygen species; OCR: oxygen consumption rate; PBS: phosphate buffer saline; PCC: pancreatic cancer cell; PDA: pancreatic ductal adenocarcinoma; RTCA: real-time cell analysis; SH2: Src Homology 2; STAT3: signal transducer and activator of transcription 3; VEGFA: vascular endothelial growth factor-α.