Role of Caspases-9 and -4 in Glycochenodeoxycholic Acid-induced Apoptosis in HepG2 Cells

Autor: Yuko Udaka, Michi Ohta, Toru Iizaka, Katsuji Oguchi, Keiichiro Ohba, Mayumi Tsuji, Hiromichi Tsuchiya, Tomoyuki Matsuoka
Rok vydání: 2009
Předmět:
Zdroj: The Showa University Journal of Medical Sciences. 21:255-267
ISSN: 2185-0968
0915-6380
Popis: It is believed that hepatocellular damage in human chronic cholestatic liver diseases is caused by the accumulation of hydrophobic bile acids, such as glycochenodeoxycholic acid(GCDCA). Previous reports have shown that GCDCA-induced apoptosis is promoted by both mitochondria-mediated and endoplasmic reticulum(ER)stress-associated pathways in HepG2 cells and that these two pathways are linked by the action of caspase-8 on BAP31. However, the interdependence of multiple pathways remains poorly understood and the role of caspases is unclear. Thus, in the present study, we investigated the interactions among the executioner caspases in GCDCA-induced apoptotic HepG2 cells. Cells were treated for 1-24 h with GCDCA(300μM), in the presence or absence of inhibitors of caspase-9, -4 or -3(each at 30μM). Pretreatment of cells with the caspase-9 inhibitor significantly suppressed GCDCA-induced apoptosis ; however, pretreatment of cells with the caspase-4 inhibitor had no effect. Furthermore, pretreatment of cells with the caspase-9 inhibitor significantly reduced GCDCA-induced increases in caspase-3 and -4 activity, as well as the mRNA expression of BiP, a molecular chaperone located in the ER. In contrast, pretreatment of cells with the caspase-4 inhibitor had no effect. These results suggest that, in GCDCA-treated HepG2 cells, caspase-4 acts downstream of both the proapoptotic Bcl-2 protein Bax and caspase-9. Because the major mechanism underlying GCDCA-induced apoptosis involves a mitochondria-mediated pathway, it is unlikely that caspase-4 has a major role in the initiation and promotion of GCDCA-induced apoptosis.
Databáze: OpenAIRE
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