Abstract
BackgroundSalinomycin is a monocarboxylic polyether antibiotic and is a potential chemotherapy drug. Our previous studies showed that salinomycin inhibited cell growth and targeted CSCs in prostate cancer. However, the precise target of salinomycin action is unclear.MethodsIn this work, we analyzed and identified differentially expressed genes (DEGs) after treatment with or without salinomycin using a gene expression microarray in vitro (PC-3 cells) and in vivo (NOD/SCID mice xenograft model generated from implanted PC-3 cells). Western blotting and immunohistochemical staining were used to analyze the expression of ATP2A3 and endoplasmic reticulum (ER) stress biomarkers. Flow cytometry was used to analyze the cell cycle, apoptosis and intracellular Ca2+ concentration.ResultsA significantly upregulated gene, ATPase sarcoplasmatic/endoplasmatic reticulum Ca2+ transporting 3 (ATP2A3), was successfully identified. In subsequent studies, we found that ATP2A3 overexpression could trigger ER stress and exert anti-cancer effects in PC-3 and DU145 cells. ATP2A3 was slightly expressed, but the ER stress biomarkers showed strong staining in prostate cancer tissues. We also found that salinomycin could trigger ER stress, which might be related to ATP2A3-mediated Ca2+ release in PC-3 cells. Furthermore, we found that salinomycin-triggered ER stress could promote apoptosis and thus exert anti-cancer effects in prostate cancer cells.ConclusionThis study demonstrates that ATP2A3 might be one of the potential targets for salinomycin, which can inhibit Ca2+ release and trigger ER stress to exert anti-cancer effects.
Highlights
Salinomycin is a monocarboxylic polyether antibiotic and is a potential chemotherapy drug
Identification of differentially expressed genes (DEGs) induced by salinomycin in vitro and in vivo Previously, we found that salinomycin inhibited PC-3 cell proliferation and decreased xenograft tumor size [5]
To investigate the mechanism of salinomycin, a microarray analysis was used to identify differentially expressed genes (DEGs) in vitro (PC-3 cells) and in vivo (NOD/SCID mice xenograft model generated from implanted PC-3 cells) (Fig. 1a)
Summary
Salinomycin is a monocarboxylic polyether antibiotic and is a potential chemotherapy drug. Salinomycin is found to inhibit the Wnt/β-catenin signaling pathway and selectively induces apoptosis [8, 9]; Zhang et al BMC Cancer (2019) 19:381 reduce the activity of ABC transporters [10]; induce oxidative stress [11], autophagy [12, 13], and anti-angiogenic and anti-tumorigenic activities [14]; inhibit EMT (Epithelial-mesenchymal transition) [15]; and inhibit cancer cell growth [16, 17] Despite all of this evidence, the molecular mechanism for salinomycin remains elusive, and the precise target of salinomycin action is unclear
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