Abstract
Erianin, a natural product derived from Dendrobium chrysotoxum Lindl, has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. In vivo, we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.
Highlights
Ferroptosis is a newly defined form of regulated cell death, which is characterized by iron-dependent peroxidation of the lipid membrane induced by reactive oxygen species (ROS) (Yu et al, 2020)
In order to explore the antitumor potential of erianin in bladder cancer, erianin was treated with different concentrations for 24 h in KU-19–19 and RT4 cells, and the cell growth potential was evaluated by CCK-8 assay
In order to determine whether erianin could inhibit the growth of bladder cancer cells by inducing the cell death, we performed Annexin V-FITC/PI staining and analyzed by flow cytometry
Summary
Ferroptosis is a newly defined form of regulated cell death, which is characterized by iron-dependent peroxidation of the lipid membrane induced by reactive oxygen species (ROS) (Yu et al, 2020). Increasing evidence show that several natural compounds can either induce or inhibit ferroptosis, further expanding their therapeutic potentials. Erianin, extracted from rare traditional Chinese medicine Dendrobium chrysotoxum Lindl, was a small-molecule natural compound with a wide range of anticancer potential. Erianin has been reported to inhibit colorectal cancer cells growth by downregulating the transcriptional activity of β-catenin (Sun et al, 2020), induce apoptosis in nasopharyngeal carcinoma by decreasing the phosphorylation of ERK1/2 (Liu et al, 2019), and suppress bladder cancer cell growth through JNK pathways and the mitochondrial apoptosis (Zhu et al, 2004). Erianin inhibited the growth and migration via inducing Ca/CaM-dependent ferroptosis and inhibiting cell migration in lung cancer cells (Chen et al, 2020a). The underlying molecular mechanism and the anticancer effect of erianin are not well exploited in bladder cancer
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