Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1

被引:8
作者
Ye, Shiying [1 ]
Hu, Xiangyan [1 ]
Sun, Shaowei [1 ,2 ]
Su, Bo [1 ,2 ]
Cai, Jiye [3 ]
Jiang, Jinhuan [1 ,2 ]
机构
[1] Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang Med Sch, Hengyang, Hunan, Peoples R China
[2] Univ South China, Sch Pharmaceut Sci, Hengyang Med Sch, Hunan Prov Key Lab Tumor Microenvironm Respons Dru, Hengyang, Hunan, Peoples R China
[3] Jinan Univ, Dept Chem, Guangzhou 510632, Peoples R China
基金
湖南省自然科学基金;
关键词
Oridonin; Ferroptosis; Oxidative stress; JNK/Nrf2/HO-1; Breast cancer; DEATH;
D O I
10.1016/j.ejphar.2024.176620
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by cotreatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI cotreatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.
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页数:12
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共 42 条
[1]   Ferroptosis in Cancer Cell Biology [J].
Bebber, Christina M. ;
Mueller, Fabienne ;
Clemente, Laura Prieto ;
Weber, Josephine ;
von Karstedt, Silvia .
CANCERS, 2020, 12 (01)
[2]   Curcumin suppresses tumorigenesis by ferroptosis in breast cancer [J].
Cao, Xuelei ;
Li, Yao ;
Wang, Yongbin ;
Yu, Tao ;
Zhu, Chao ;
Zhang, Xuezhi ;
Guan, Jialiang .
PLOS ONE, 2022, 17 (01)
[3]   CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway [J].
Chen, Meng-Shian ;
Wang, Sheng-Fan ;
Hsu, Chih-Yi ;
Yin, Pen-Hui ;
Yeh, Tien-Shun ;
Lee, Hsin-Chen ;
Tseng, Ling-Ming .
ONCOTARGET, 2017, 8 (70) :114588-114602
[4]   Breast Cancer Genetics: Diagnostics and Treatment [J].
Criscitiello, Carmen ;
Corti, Chiara .
GENES, 2022, 13 (09)
[5]   Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1a [J].
Dai, Jie-min ;
Sun, Ke ;
Li, Chang ;
Cheng, Min ;
Guan, Jun-hua ;
Yang, Li-na ;
Zhang, Li-wen .
CLINICAL & TRANSLATIONAL ONCOLOGY, 2023, 25 (06) :1606-1616
[6]   JNK Pathway in CNS Pathologies [J].
de los Reyes Corrales, Teresa ;
Losada-Perez, Maria ;
Casas-Tinto, Sergio .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2021, 22 (08)
[7]   Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death [J].
Dixon, Scott J. ;
Lemberg, Kathryn M. ;
Lamprecht, Michael R. ;
Skouta, Rachid ;
Zaitsev, Eleina M. ;
Gleason, Caroline E. ;
Patel, Darpan N. ;
Bauer, Andras J. ;
Cantley, Alexandra M. ;
Yang, Wan Seok ;
Morrison, Barclay, III ;
Stockwell, Brent R. .
CELL, 2012, 149 (05) :1060-1072
[8]   Molecular Docking and Structure-Based Drug Design Strategies [J].
Ferreira, Leonardo G. ;
dos Santos, Ricardo N. ;
Oliva, Glaucius ;
Andricopulo, Adriano D. .
MOLECULES, 2015, 20 (07) :13384-13421
[9]   The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer [J].
Hammouda, Manel B. ;
Ford, Amy E. ;
Liu, Yuan ;
Zhang, Jennifer Y. .
CELLS, 2020, 9 (04)
[10]   The development of the concept of ferroptosis [J].
Hirschhorn, Tal ;
Stockwell, Brent R. .
FREE RADICAL BIOLOGY AND MEDICINE, 2019, 133 :130-143