|Title:||Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation||Authors:||Kao, C.
|Issue Date:||2014||Journal Volume:||5||Journal Issue:||11||Source:||Cell Death and Disease||Abstract:||
The antitumor activity of an inhibitor of 26S proteasome bortezomib (Velcade) has been observed in various malignancies, including colon cancer, prostate cancer, breast cancer, and ovarian cancer. Bortezomib has been proposed to stimulate autophagy, but scientific observations did not always support this. Interactions between ERK activity and autophagy are complex and not completely clear. Autophagy proteins have recently been shown to regulate the functions of ERK, and ERK activation has been found to induce autophagy. On the other hand, sustained activation of ERK has also been shown to inhibit the maturation step of the autophagy process. In this study, we sought to identify the mechanism of autophagy regulation in cancer cells treated with bortezomib. Our results indicate that bortezomib blocked the autophagic flux without inhibiting the fusion of the autophagosome and lysosome. In ovarian cancer, as well as endometrial cancer and hepatocellular carcinoma cells, bortezomib inhibited protein degradation in lysosomes by suppressing cathepsins, which requires the participation of ERK phosphorylation, but not JNK or p38. Our findings that ERK phosphorylation reduced cathepsins further explain how ERK phosphorylation inhibits the autophagic flux. In conclusion, bortezomib may induce ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy in ovarian cancer and other solid tumors. The inhibition of cisplatin-induced autophagy by bortezomib can enhance chemotherapy efficacy in ovarian cancer. As we also found that bortezomib blocks the autophagic flux in other cancers, the synergistic cytotoxic effect of bortezomib by abolishing chemotherapy-related autophagy may help us develop strategies of combination therapies for multiple cancers. ? 2014 Macmillan Publishers Limited All rights reserved.
|DOI:||10.1038/cddis.2014.468||SDG/Keyword:||autophagy protein 12; autophagy protein 5; beclin 1; benzyloxycarbonylleucylleucylleucinal; bortezomib; cathepsin B; cathepsin D; cathepsin G; cisplatin; cycloheximide; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase p38; peptides and proteins; protein c jun; protein p62; unclassified drug; antineoplastic agent; benzyloxycarbonylleucyl-leucyl-leucine aldehyde; boronic acid derivative; bortezomib; cisplatin; leupeptin; mitogen activated protein kinase; mitogen activated protein kinase kinase 4; mitogen activated protein kinase p38; proteasome inhibitor; pyrazine derivative; animal cell; antineoplastic activity; Article; autolysosome; autophagosome; autophagy; controlled study; drug inhibition; endometrium cancer; enzyme activation; enzyme phosphorylation; female; human; human cell; immunohistochemistry; liver cell carcinoma; nonhuman; ovary cancer; priority journal; protein degradation; protein expression; antagonists and inhibitors; autophagy; cell survival; drug effects; gene expression regulation; genetics; metabolism; Ovarian Neoplasms; pathology; phagosome; phosphorylation; signal transduction; tumor cell line; Antineoplastic Agents; Autophagy; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Survival; Cisplatin; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Leupeptins; MAP Kinase Kinase 4; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Phagosomes; Phosphorylation; Proteasome Inhibitors; Pyrazines; Signal Transduction
|Appears in Collections:||生命科學系|
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