title: Reactive oxygen species-mediated activation of the Src-epidermal growth factor receptor-Akt signaling cascade prevents bortezomib-induced apoptosis in hepatocellular carcinoma cells.
abstract: Proteasomes are essential for numerous cellular processes, including the cell cycle, regulation of gene expression and responses to cellular stress. Proteasome inhibitors are promising anticancer agents. The proteasome inhibitor bortezomib effectively suppresses certain types of cancer, including multiple myeloma and mantle cell lymphoma. However, bortezomib poorly inhibits solid tumors, including hepatocellular carcinoma. The activation of Akt represents an adaptive response that prevents bortezomib-induced cell apoptosis. In the present study, bortezomib induced phosphorylation of EGFR, Src and Akt in hepatoma cells and inhibition of Src reduced bortezomib-induced EGFR and Akt phosphorylation. Treatment of hepatoma cells with bortezomib led to an increase in the levels of intracellular reactive oxygen species (ROS). The ROS scavenger N-acetyl-L-cysteine inhibits bortezomib-induced ROS production and abrogates the phosphorylation of Src, epidermal growth factor receptor and Akt. The combination of bortezomib and saracatinib, a Src inhibitor, synergistically induced hepatoma cell apoptosis. The present study concluded that ROS mediated the activation of the Src-EGFR-Akt cascade by bortezomib. The combination of the Src inhibitor and bortezomib holds promise in the treatment of hepatocellular carcinoma.
authors.affiliation: State Key Labaoratory of Biotherapy, Section of Oncogene, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Hou
authors.affiliation: State Key Labaoratory of Biotherapy, Section of Oncogene, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Anguo
authors.initials: A
authors.lastname: Cui
authors.affiliation: State Key Labaoratory of Biotherapy, Section of Oncogene, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Peiying
authors.initials: P
authors.lastname: Song
authors.affiliation: Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Hua
authors.affiliation: Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.affiliation: State Key Labaoratory of Biotherapy, Section of Oncogene, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yangfu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D011799:Quinazolines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib