Ebselen impairs cellular oxidative state and induces endoplasmic reticulum stress and activation of crucial mitogen‐activated protein kinases in pancreatic tumour AR42J cells

Abstract

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is an organoselenium radical scavenger compound, which has strong antioxidant and anti-inflammatory effects. However, evidence suggests that this compound could exert deleterious actions on cell physiology. In this study, we have analyzed the effect of ebselen on rat pancreatic AR42J cells. Cytosolic free-Ca concentration ([Ca ] ), cellular oxidative status, setting of endoplasmic reticulum stress, and phosphorylation of major mitogen-activated protein kinases were analyzed. Our results show that ebselen evoked a concentration-dependent increase in [Ca ] . The compound induced an increase in the generation of reactive oxygen species in the mitochondria. We also observed an increase in global cysteine oxidation in the presence of ebselen. In the presence of ebselen an impairment of cholecystokinin-evoked amylase release was noted. Moreover, involvement of the unfolded protein response markers, ER chaperone and signaling regulator GRP78/BiP, eukaryotic translation initiation factor 2α and X-box binding protein 1 was detected. Finally, increases in the phosphorylation of SAPK/JNK, p38 MAPK, and p44/42 MAPK in the presence of ebselen were also observed. Our results provide evidences for an impairment of cellular oxidative state and enzyme secretion, the induction of endoplasmic reticulum stress and the activation of crucial mitogen-activated protein kinases in the presence of ebselen. As a consequence ebselen exerts a potential toxic effect on AR42J cells.

Antitumor effects and mechanisms of pyropheophorbide‑α methyl ester‑mediated photodynamic therapy on�the human osteosarcoma cell line MG‑63

“…ERS triggers an unfolded protein response and intracellular calcium homeostasis imbalance and increases the level of protein phosphorylation or expression by activating the endoplasmic reticulum transmembrane proteins PERK, IRE1α, and ATF6; this step activates downstream signaling molecules or gene expression and maintains cell homeostasis, which is essential for cell survival. However, persistent or excessive ERS promotes the expression of endoplasmic reticulum-associated death proteins and induces apoptosis (49)(50)(51)(52). In the present study, the level of intracellular calcium in MG-63 cells was significantly increased after 3-h MPPa-PdT treatment.…”

The melatonin receptor antagonist luzindole induces the activation of cellular stress responses and decreases viability of rat pancreatic stellate cells

“…Involvement of the MAPK signaling network to regulate cell survival or death responses following ER stress has been shown (Darling & Cook, 2014; Dufey, Sepulveda, Rojas‐Rivera, & Hetz, 2014). Moreover, the relationship between ER stress and the activation of p38‐MAPK has been previously suggested in other cell types, e.g., lung cells (Mijošek et al, 2016), hepatocytes (Imarisio et al, 2017), brain (Wei et al, 2016), pancreatic β‐cells (Šrámek et al, 2017) or AR42J cells (Santofimia‐Castaño et al, 2018). Therefore, activation of ER stress by lunzidole is probably linked to MAPKs signaling involving p38.…”

Effect and mechanisms of celastrol on the apoptosis of HOS osteosarcoma cells

“…The concentration of calcium ions in the cytoplasm increases when the ER is damaged. Following treatment with celastrol, evident swelling and dysfunction of the ER appeared, with a significant increase in the cytoplasmic free calcium ion level, which indicated that the ER of HOS cells was damaged (22)(23)(24)(25). The ER is also the receptor of cellular stress.…”