Low-intensity pulsed ultrasound and oridonin synergistically induce ferroptosis of pancreatic cancer cells by activating PIEZO1 via the Nrf2/HO-1/GPX4 pathway.
10.12122/j.issn.1673-4254.2025.10.12
- Author:
Bihang SUN
1
;
Yujun GUO
1
;
Yulin QI
2
;
Dan YAO
1
;
Wenzhi CHEN
1
;
Nianzhi CHEN
1
Author Information
1. State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China.
2. Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
- Publication Type:Journal Article
- Keywords:
ferroptosis;
low-intensity pulsed ultrasound;
oridonin;
pancreatic cancer;
piezo1
- MeSH:
Ferroptosis/drug effects*;
Animals;
Pancreatic Neoplasms/metabolism*;
NF-E2-Related Factor 2/metabolism*;
Humans;
Cell Line, Tumor;
Mice;
Heme Oxygenase-1/metabolism*;
Diterpenes, Kaurane/pharmacology*;
Cell Proliferation/drug effects*;
Mice, Inbred C57BL;
Phospholipid Hydroperoxide Glutathione Peroxidase;
Ion Channels/metabolism*;
Ultrasonic Waves;
Signal Transduction
- From:
Journal of Southern Medical University
2025;45(10):2160-2170
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVES:To evaluate the inhibitory effect of oridonin against proliferation of pancreatic cancer cells and the mechanism underlying the synergistic effect of low-intensity pulsed ultrasound (LIPUS).
METHODS:PANC-1 cells treated with different concentrations of oridonin were examined for changes in cell proliferation using CCK-8 assay and in MDA, GSH and ATP levels using flow cytometry. The protein expressions of GPX4, Nrf2 and HO-1 in the treated cells were detected with Western blotting. The effect of Fer-1, a ferroptosis inhibitor, on proliferation of oridonin-treated cells were assessed, and the effects of oridonin combined with LIPUS on PIEZO1 protein expression was evalauted using Western blotting. A C57BL/6J mouse model bearing pancreatic cancer cell xenograft was established and treated with oridonin, LIPUS, or both, and the histological changes in the tumor tissues and tumor cell proliferation were examined with HE staining and immunohistochemistry for Ki67; the changes in GPX4 expression in the tumor tissues were detected using Western blotting and immunofluorescence staining.
RESULTS:In PANC-1 cells, oridonin treatment significantly inhibited cell proliferation, increased intracellular Fe2+, ROS, and MDA levels, and decreased GSH and ATP levels. Oridonin also resulted in lowered GPX4 and increased HO-1 and Nrf2 protein expression levels in the cells. The combined treatment with LIPUS signficiantly enhanced the inhibitory effect of oridonin on PANC-1 cell viability in vitro and on xenograft growth in the mouse models, resulting also in more obvious reduction of the intensity of Ki67 staining and GPX4 protein expression and more pronounced increase of PIEZO1 protein expression in the tumor tissues in the mouse models.
CONCLUSIONS:LIPUS enhances the effect of oridonin to promote ferroptosis of pancreatic cancer cells by activating PIEZO1 through the Nrf2/HO-1/GPX4 pathway.
