Abstract
In this study, we investigated the antitumor activity of icariin (ICA) in human esophageal squamous cell carcinoma (ESCC) in vitro and in vivo and explored the role of endoplasmic reticulum stress (ERS) signaling in this activity. ICA treatment resulted in a dose- and time-dependent decrease in the viability of human EC109 and TE1 ESCCs. Additionally, ICA exhibited strong antitumor activity, as evidenced by reductions in cell migration, adhesion, and intracellular glutathione (GSH) levels and by increases in the EC109 and TE1 cell apoptotic index, Caspase 9 activity, reactive oxygen species (ROS) level, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Furthermore, ICA treatments upregulated the levels of ERS-related molecules (p-PERK, GRP78, ATF4, p-eIF2α, and CHOP) and a pro-apoptotic protein (PUMA) and simultaneously downregulated an anti-apoptotic protein (Bcl2) in the two ESCC cell lines. The downregulation of ERS signaling using eIF2α siRNA desensitized EC109 and TE1 cells to ICA treatment, and the upregulation of ERS signaling using thapsigargin sensitized EC109 and TE1 cells to ICA treatment. In summary, ERS activation may represent a mechanism of action for the anticancer activity of ICA in ESCCs, and the activation of ERS signaling may represent a novel therapeutic intervention for human esophageal cancer.
Highlights
Found in vegetables, fruit, and beverages of plant origin and are well known for their anti-inflammatory, analgesic, and physiologically antipyretic activities[6]
The outcome of unfolded protein response (UPR) activation involves the transient attenuation of protein synthesis, an increased capacity for protein trafficking through the endoplasmic reticulum (ER) and increased protein folding, transport, and degradation via processes such as ER-associated degradation (ERAD) and autophagy[18]
Three ER membrane-associated proteins act as ERS sensors: (1) inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), (2) the double-stranded RNA (PKR)-activated protein kinase-like eukaryotic translation initiation factor 2α kinase (PERK), and (3) activating transcription factor 6 (ATF6)[19]
Summary
Found in vegetables, fruit, and beverages of plant origin and are well known for their anti-inflammatory, analgesic, and physiologically antipyretic activities[6]. Three ER membrane-associated proteins act as ERS sensors: (1) inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1), (2) the double-stranded RNA (PKR)-activated protein kinase-like eukaryotic translation initiation factor 2α (eIF2α ) kinase (PERK), and (3) activating transcription factor 6 (ATF6)[19] Under normal circumstances, these sensors are maintained in an inactive state due to their binding to the chaperone glucose-regulated protein 78 (GRP78), which forms a large multiprotein complex with a set of other ER molecular chaperones, including the heat shock protein of 90 kDa (Hsp90) ER homolog, Grp[94]; protein disulfide isomerase; calcium binding protein; and cyclophilin B20. In many ERS pathways, the PERK, IRE1, and ATF6 signaling axes induce the activation of CHOP, eIF2α , and p53 upregulated modulator of apoptosis (PUMA, a member of the Bcl[2] protein family), respectively, to sensitize cells to ERS-induced cell death[27]. We assessed the anticancer activity of ICA in ESCC and explored the role of ERS signaling in this activity
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