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Article: Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis

TitleAlisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis
Authors
Issue Date2010
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
Citation
Molecular Cancer Therapeutics, 2010, v. 9 n. 3, p. 718-730 How to Cite?
AbstractEmerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. ©2010 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/70188
ISSN
2015 Impact Factor: 5.579
2015 SCImago Journal Rankings: 3.224
ISI Accession Number ID
Funding AgencyGrant Number
University Grants Committee of the Hong Kong Special Administrative RegionAoE/P-10/01
University of Hong Kong
Funding Information:

Grant Support

References
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DC FieldValueLanguage
dc.contributor.authorLaw, BYKen_HK
dc.contributor.authorWang, Men_HK
dc.contributor.authorMa, DLen_HK
dc.contributor.authorAlMousa, Fen_HK
dc.contributor.authorMichelangeli, Fen_HK
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorNg, MHLen_HK
dc.contributor.authorTo, KFen_HK
dc.contributor.authorMok, AYFen_HK
dc.contributor.authorKo, RYYen_HK
dc.contributor.authorLam, SKen_HK
dc.contributor.authorChen, Fen_HK
dc.contributor.authorChe, CMen_HK
dc.contributor.authorChiu, Pen_HK
dc.contributor.authorKo, BCBen_HK
dc.date.accessioned2010-09-06T06:20:32Z-
dc.date.available2010-09-06T06:20:32Z-
dc.date.issued2010en_HK
dc.identifier.citationMolecular Cancer Therapeutics, 2010, v. 9 n. 3, p. 718-730en_HK
dc.identifier.issn1535-7163en_HK
dc.identifier.urihttp://hdl.handle.net/10722/70188-
dc.description.abstractEmerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. ©2010 AACR.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/en_HK
dc.relation.ispartofMolecular Cancer Therapeuticsen_HK
dc.subject.meshApoptosis - drug effects-
dc.subject.meshAutophagy - drug effects-
dc.subject.meshCholestenones - pharmacology-
dc.subject.meshEndoplasmic Reticulum - drug effects - pathology-
dc.subject.meshSarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists and inhibitors-
dc.titleAlisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosisen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1535-7163&volume=9&issue=3&spage=718&epage=730&date=2010&atitle=Alisol+B,+a+novel+inhibitor+of+the+sarcoplasmic/endoplasmic+reticulum+Ca2++ATPase+pump,+induces+autophagy,+endoplasmic+reticulum+stress,+and+apoptosisen_HK
dc.identifier.emailWang, M: mfwang@hku.hken_HK
dc.identifier.emailMa, DL: edmondma@hku.hken_HK
dc.identifier.emailLam, SK: secant@hku.hken_HK
dc.identifier.emailChen, F: sfchen@hku.hken_HK
dc.identifier.emailChe, CM: cmche@hku.hken_HK
dc.identifier.emailChiu, P: pchiu@hku.hken_HK
dc.identifier.authorityWang, M=rp00800en_HK
dc.identifier.authorityMa, DL=rp00760en_HK
dc.identifier.authorityLam, SK=rp00720en_HK
dc.identifier.authorityChen, F=rp00672en_HK
dc.identifier.authorityChe, CM=rp00670en_HK
dc.identifier.authorityChiu, P=rp00680en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/1535-7163.MCT-09-0700en_HK
dc.identifier.pmid20197400-
dc.identifier.scopuseid_2-s2.0-77949736802en_HK
dc.identifier.hkuros169749en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77949736802&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume9en_HK
dc.identifier.issue3en_HK
dc.identifier.spage718en_HK
dc.identifier.epage730en_HK
dc.identifier.isiWOS:000278487300018-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectInstitute of molecular technology for drug discovery and synthesis-
dc.identifier.scopusauthoridLaw, BYK=36150915000en_HK
dc.identifier.scopusauthoridWang, M=7406691844en_HK
dc.identifier.scopusauthoridMa, DL=7402075538en_HK
dc.identifier.scopusauthoridAlMousa, F=24823826900en_HK
dc.identifier.scopusauthoridMichelangeli, F=7005383773en_HK
dc.identifier.scopusauthoridCheng, SH=7404681588en_HK
dc.identifier.scopusauthoridNg, MHL=35292609300en_HK
dc.identifier.scopusauthoridTo, KF=7101911940en_HK
dc.identifier.scopusauthoridMok, AYF=36151223500en_HK
dc.identifier.scopusauthoridKo, RYY=36150930100en_HK
dc.identifier.scopusauthoridLam, SK=8560491900en_HK
dc.identifier.scopusauthoridChen, F=7404907980en_HK
dc.identifier.scopusauthoridChe, CM=7102442791en_HK
dc.identifier.scopusauthoridChiu, P=11140148700en_HK
dc.identifier.scopusauthoridKo, BCB=7102833927en_HK

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