It has been shown that drug resistance is extremely common in hepatocellular carcinoma (HCC) and is one of the major problems in HCC chemotherapy. However, the detailed mechanisms remain largely unknown. We have previously shown that endoplasmic reticulum (ER) stress is involved in the tumorigenesis of HCC. Here, we demonstrated that the unfolded protein response (UPR) inhibits cisplatin-induced HCC cell apoptosis. In HCC cells, cisplatin treatment triggers the UPR, which subsequently inhibits cisplatin-induced apoptosis. Importantly, mild ER stress precondition suppresses the sensitivity of HCC cells to cisplatin-induced apoptosis through autophagy regulation. Furthermore, heat-shock protein 27 (Hsp27) is involved in the cytoprotective role of the UPR in cisplatin-induced apoptosis. We also demonstrated that Hsp27 inhibits cisplatin- induced HCC cell death through autophagy activation. Taken together, our results indicate that the UPR inhibits cisplatin-induced apoptosis in HCC cells, at least in part, by Hsp27-mediated autophagy activation.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza fyziologie   účinky léků   MeSH
• autofagie fyziologie   účinky léků   MeSH
• cisplatina farmakologie   metabolismus   MeSH
• dithiothreitol farmakologie   MeSH
• endoplazmatické retikulum fyziologie   účinky léků   MeSH
• hepatocelulární karcinom patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory jater patologie   MeSH
• proteiny tepelného šoku HSP27 genetika   metabolismus   MeSH
• reakce na tepelný šok MeSH
• signální dráha UPR fyziologie   MeSH
• tunikamycin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

The potential pro-survival role of phosphatidylinositol 3-kinase (PI3K)/Akt during endoplasmic reticulum stress has been well-characterized. However, the detailed mechanisms remain largely unknown. Here, we showed that PI3K/Akt inhibition promoted endoplasmic reticulum stress-induced apoptosis in a glucose-regulated protein 78 (GRP78)-dependent manner. During endoplasmic reticulum stress, high levels of Akt phosphorylation were sustained for at least 18 h in HEK293 cells. Importantly, PI3K/Akt enhanced GRP78 accumulation through increasing its stability following endoplasmic reticulum stress. Furthermore, Akt1, but not Akt2 or Akt3, was involved in GRP78 stability regulation. These results suggest that PI3K/Akt inhibits endoplasmic reticulum stress-induced apoptosis in HEK293 cells, at least in part, by promoting GRP78 protein stability.

• MeSH
• apoptóza fyziologie   účinky léků   MeSH
• buněčné linie MeSH
• buňky NIH 3T3 MeSH
• dithiothreitol farmakologie   MeSH
• endoplazmatické retikulum metabolismus   účinky léků   MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• fyziologický stres MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• myši MeSH
• proteiny tepelného šoku genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• thapsigargin farmakologie   MeSH
• transkripční faktor CHOP metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH