Research Paper Volume 12, Issue 7 pp 6240—6259
Inhibition of esophageal-carcinoma cell proliferation by genistein via suppression of JAK1/2-STAT3 and AKT/MDM2/p53 signaling pathways
- 1 Department of Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen 361003, Fujian Province, P.R. China
- 2 School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, P.R. China
- 3 Department of Medical Oncology, Cancer Center, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen 361003, Fujian Province, P.R. China
- 4 Department of Radiation Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, P.R. China
- 5 Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, P.R. China
received: November 13, 2019 ; accepted: March 3, 2020 ; published: April 10, 2020 ;https://doi.org/10.18632/aging.103019
How to Cite
Copyright © 2020 Gao 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.
Esophageal carcinoma (EsC) is a clinically challenging neoplastic disease. Genistein, a natural isoflavone product, has anti-tumor properties. Through in vitro and in vivo studies, we found that genistein suppressed EsC cell proliferation in a time- and concentration-dependent manner. In addition, genistein markedly promoted apoptosis and arrested cell cycle at the G0/G1 phase in a concentration-dependent manner. Furthermore, high concentrations of genistein have no adverse effect on normal esophageal epithelial cells. Mechanistically, genistein treatment strikingly reduced the expression of cell cycle-associated genes, and up-regulated the expression of cell apoptosis-related genes in EsC cells. Additionally, genistein dramatically decreased epidermal growth factor receptor (EGFR) expression and attenuated its down-stream signaling molecules STAT3, MDM2, Akt and JAK1/2 phosphorylation, resulting in inhibited nuclear translocation of STAT3 and MDM2, thereby inhibiting the JAK1/2-STAT3 and AKT/MDM2/p53 signaling pathways. In xenograft nude mice, genistein administration strikingly impaired tumor growth in a dose-dependent manner. Moreover, similar disturbances in molecular mechanisms were observed in vivo. Taken together, genistein suppressed the JAK1/2-STAT3 and AKT/MDM2/p53 signaling pathways by decreasing EGFR expression, leading to cell apoptosis, cell cycle arrest, and proliferation inhibition in EsC cells. Our findings suggest that genistein may be a promising alternative adjuvant therapy for patients with EsC.