Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling

Abstract

Salinomycin is a polyether antiprotozoal antibiotic that is widely used as an animal food additive. Some antifungal, antiparasitic, antiviral and anti-inflammatory activities have been reported for salinomycin. Recently, the anti-cancer effect of salinomycin has been demonstrated in breast cancer; however, the underlying mechanism remains unknown. The present study aimed to investigate the functional roles of salinomycin in the progression of prostate cancer cells using the DU145 and PC-3 cell lines. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression of oxidative stress and endoplasmic reticulum stress-related molecules, and flow cytometry was performed to detect the apoptosis rate of DU145 and PC-3 cells after salinomycin treatment. The results demonstrated that salinomycin inhibited the viability and induced the apoptosis of PC-3 and DU145 cells in a dose-dependent manner. Furthermore, salinomycin increased the production of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and the lipid peroxidation. In addition, salinomycin induced the activation of unfolded protein response and endoplasmic reticulum stress in DU145 and PC-3 cells, as indicated by the elevated expression of binding immunoglobulin protein, activating transcription factor 4, phosphorylated eukaryotic initiation factor 2α, phosphorylated protein kinase RNA-like endoplasmic reticulum kinase and C/EBP homologous protein.In addition, salinomycin significantly downregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 and glutamate-cysteine ligase catalytic subunit and decreased the activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase in PC-3 and DU145 cells. Furthermore, the Nrf2 activator, tert-butylhydroquinone, significantly reversed the therapeutic effects of salinomycin by stimulating the Nrf2 pathway and increasing the activity of antioxidant enzymes. Taken together, these findings demonstrated that salinomycin may trigger apoptosis by inducing oxidative and ER stress in prostate cancer cells via suppressing Nrf2 signaling.

Effects of boric acid and potassium metaborate on cytokine levels and redox stress parameters in a wound model infected with methicillin‑resistant Staphylococcus aureus

“…Geyikoglu et al ( 40 ) demonstrated that boric acid decreased the 8-OHdG expression level in ischemia reperfusion injury by acting as an antioxidant, anti-inflammatory and antiapoptotic agent. The results of TAC, TOS and LDH assays supported the results from the 8-OHdG staining assay ( 41 , 42 ).…”

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression

“…Downregulating NRF2 increases ROS, oxidation of nucleic acids and lipids, decreases the activity of antioxidant enzymes, and increases the unfolded protein response and endoplasmic reticulum stress in advanced stage PCa (J. Yu et al, 2021). A plantbased polyphenol fraction upregulated ROS levels by decreasing NRF2 and increasing monoamine oxidase A activity, both in androgen-dependent LNCaP and androgenindependent PC3 and DU145 cells but not in normal cells.…”

“…The antibiotic, salinomycin, increases apoptosis via ER and oxidative stress in advanced PCa by suppressing NRF2 activity and expression of its target genes: HO-1, NQO1 and GCLC (J. Yu et al, 2021). In TRAMPC mouse models it was observed that the (T. Y.…”

Evaluating the Effects of Separate and Concomitant Use of MK-2206 and Salinomycin on Prostate Cancer Cell Line

“…Salinomycin is a monocarboxylic ionophore antibiotic isolated from the bacterium Streptomyces albus (15). Also, there are convincing evidences regarding the antifungal, antiparasitic, antiviral and anti-inflammatory properties of this compound (15).…”

“…Salinomycin is a monocarboxylic ionophore antibiotic isolated from the bacterium Streptomyces albus (15). Also, there are convincing evidences regarding the antifungal, antiparasitic, antiviral and anti-inflammatory properties of this compound (15). Lately, the anticancer effect of salinomycin has been highlighted due to its potential in apoptosis induction and downregulating the growth of various types of chemotherapeutic-resistant cancer cells (16).…”