Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity

• Published in: Phytomedicine (Stuttgart) Vol. 118; p. 154990
• Main Authors: Ruan, Qingqing, Wen, Chunmei, Jin, Guihua, Yuan, Ziwei, Yang, Xuejia, Wen, Zhikai, Huang, Gang, Li, Guogang, Deng, Jie, Bai, Yongheng
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.09.2023
• Subjects: Apoptosis; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; Cell Proliferation; Epithelial-mesenchymal transition; Gene Expression Regulation, Neoplastic; Humans; NF-E2-Related Factor 2 - metabolism; Nrf2; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - metabolism; Phloretin; Phloretin - pharmacology; STAT3; STAT3 Transcription Factor - metabolism; PBS; RT; Pancreatic ductal adenocarcinoma; PCCs; RTCA; STAT3; EMT; Epithelial-mesenchymal transition; DMEM; PC; PDAC; Nrf2; Phloretin; FBS; ROS; CCK-8; HE; Apoptosis
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2023.154990

•Phloretin suppresses proliferation and metastasis of PCCs via devitalizing STAT3 activity.•Phloretin induces DNA damage and ROS accumulation, as well as mitochondrial-dependent apoptosis in PCCs.•Phloretin-induced STAT3 inhibition is regulated by enhancing Nrf2 activity. Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling exerts a vital effect on the growth and progression of PDAC. While dietary flavonoid phloretin has anti-inflammatory and antioxidant activities, it remains unclear whether phloretin has anti-tumor effects on PDAC. The focus of the present study is to elucidate the effects of phloretin on PDAC and investigate its underlying molecular mechanisms. Effect of phloretin were assessed in the pancreatic cancer cells (PCCs) by colony formation assay, real-time cell analysis, flow cytometry, Immunofluorescence staining, and cell migration assay. The expressions of mRNA and protein were respectively analyzed by quantitative PCR and Western blotting. A xenograft model was used to appraise the antitumor efficacy of phloretin. Phloretin treatment significantly restrained cell viability and metastasis, induced DNA injury and ROS accumulation, and triggered mitochondrial-dependent apoptosis in PCCs. Mechanistically, phloretin exhibits anti-tumor potential via inactivating STAT3 signaling and enhancing Nrf2 activity. STAT3 overexpression and Nrf2 silencing partially relieved phloretin-induced inhibition on cell growth and metastasis in PCCs. Phloretin remarkably blocked pancreatic tumor growth and metastasis in vivo. Phloretin suppresses pancreatic cancer growth and progression through inhibition of STAT3 mediated by enhancing Nrf2 activity. Phloretin may serve as a promising therapeutic agent for PDAC.