Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa.
Oplopantriol-A (OPT) is a natural polyyne from Oplopanax horridus. We show here that OPT preferentially kills cancer cells and inhibits tumor growth. We demonstrate that OPT-induced cancer cell death is mediated by excessive endoplasmic reticulum (ER) stress. Decreasing the level of ER stress either by inactivating components of the unfolded protein response (UPR) pathway or by expression of ER chaperone protein glucose-regulated protein 78 (GRP78) decreases OPT-induced cell death. We show that OPT induces the accumulation of ubiquitinated proteins and the stabilization of unstable proteins, suggesting that OPT functions, at least in part, through interfering with the ubiquitin/proteasome pathway. In support of this, inhibition of protein synthesis significantly decreased the accumulation of ubiquitinated proteins, which is correlated with significantly decreased OPT-induced ER stress and cell death. Finally, we show that OPT treatment significantly induced the expression of BH3-only proteins, Noxa and Bim. Knockdown of both Noxa and Bim significantly blocked OPT-induced cell death. Taken together, our results suggest that OPT is a potential new anticancer agent that induces cancer cell death through inducing ER stress and BH3 proteins Noxa and Bim.
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
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Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
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Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
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1] Tang Center for Herbal Medicine Research, The University of Chicago, Chicago, IL, USA [2] Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL, USA.
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Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
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1] Tang Center for Herbal Medicine Research, The University of Chicago, Chicago, IL, USA [2] Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL, USA.
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State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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1] Tang Center for Herbal Medicine Research, The University of Chicago, Chicago, IL, USA [2] Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL, USA.
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Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D053279:Polyynes / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C000597685:9,17-octadecadien-12,14- diyne-1,11,16-triol; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D057149:Ubiquitinated Proteins; D053279:Polyynes