Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation.
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.
1] Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan [2] Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Kao
Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Chao
Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Tsai
1] Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan [2] Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Chuang
Department of Life Science, National Taiwan University, Taipei, Taiwan.
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Huang
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
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Chen
Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Lin
1] Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan [2] Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan [3] Genomic Medicine Research Core Laboratory, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan [4] School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Wang
1] Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan [2] Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Wang
Department of Obstetrics and Gynecology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Lai
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D007976:Leupeptins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde