Tunicamycin Induces Hepatic Stellate Cell Apoptosis Through Calpain-2/Ca2 +-Dependent Endoplasmic Reticulum Stress Pathway

Abstract

It has been reported that calpain/caspase-mediated apoptosis induced by endoplasmic reticulum stress (ERS) in hepatic stellate cells (HSCs) by previous studies. At present, the activation of HSC is an important cause of liver fibrosis, and the induction of HSC apoptosis plays an irreplaceable role in reversing liver fibrosis. Therefore, it is of great significance to explore mechanisms of action that can induce HSC apoptosis for the reversal of hepatic fibrosis and the clinical prevention and treatment of hepatic-fibrosis-related diseases such as hepatitis, cirrhosis, and liver cancer. In the current study, we demonstrated that tunicamycin (a novel ERS inducer) can induce the apoptosis of HSCs and increase the concentration of intracellular Ca2+ and the expression of ERS protein GRP78, apoptosis protein caspase-12, and Bax, while it can decrease the antiapoptosis protein expression of Bcl-2. Our findings indicate that tunicamycin can induce HSCs apoptosis through calpain-2/Ca2+-dependent ERS pathway.

Melatonin alleviates PM2.5‐induced glucose metabolism disorder and lipidome alteration by regulating endoplasmic reticulum stress

“…ER is an important Ca 2+ reservoir in cells. When cells are affected by exogenous compounds, ER stress occurs due to the disorder of calcium ion metabolism and function 38 . Therefore, ER stress induced by DNAJB9 might be partly mediated by DNAJB9's regulation of Ca 2+ .…”

Gemigliptin alleviates succinate induced endoplasmic reticulum stress and activation of hepatic stellate cells

“…At high doses, tunicamycin increased ER stress markers but it reduced viability and migration of LX-2 cells. Tunicamycin is known as a potent ER stress inducer which can lead to HSC activation [40] but severe UPR with high dosage can also result in apoptosis [41,42]. One study showed that primary mouse HSCs which were cultured on plastic dish underwent activation from day fourth while UPR genes were induced just after 2 h. UPR was also seen earlier than the up-regulation of activation markers in freshly isolated HSCs from mice received single dose of CCl 4 , suggesting UPR is expressed early during HSC activation [43].…”

Calpain-2 Facilitates Autophagic/Lysosomal Defects and Apoptosis in ARPE-19 Cells and Rats Induced by Exosomes from RPE Cells under NaIO3 Stimulation

“…Calpain-2 also plays a pivotal role in the tumor necrosis factor- (TNF-) α -induced autophagy in mouse hippocampal neurons [ 16 ]. Moreover, the tunicamycin-mediated calpain-2-dependent endoplasmic reticulum stress pathway leads to hepatic stellate cell apoptosis [ 17 ]. In addition, it has been reported that calpain-2 is involved in neuronal apoptosis induced by polybrominated diphenyl ether-153 [ 18 ].…”