title: Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway.
abstract: We previously isolated cacalol as a free radical-scavenging compound from Cacalia delphiniifolia which is a traditional Asian herbal plant and is believed to have medicinal effects on cancer. In this report, we demonstrated that cacalol has strong anti-proliferation effect on breast cancer cells and induces apoptosis by activating a pro-apoptotic pathway. We also found that a combination of cacalol and other chemotherapeutic drugs (Taxol and cyclophosphamide) synergistically induced apoptosis and partially overcame chemo-resistance. To further gain a mechanistic insight, we tested a potential inhibitory effect of cacalol on fatty acid synthase gene (FAS) in breast cancer cells, and found that cacalol significantly modulated the expression of the FAS gene, which resulted in apoptosis through activation of DAPK2 and caspase 3. We have also shown that cacalol significantly suppressed the Akt-sterol regulatory element-binding proteins (SREBP) signaling pathway and concomitant transcriptional activation of FAS. In a xenograft model of nude mouse, when cacalol was administered intraperitoneally, tumor growth was significantly suppressed. Importantly, oral administration of cacalol before implanting tumors showed significant preventive effect on tumor growth in the same animal model. Furthermore, the treatment of mice with a combination of low dose of Taxol and cacalol significantly suppressed the tumor growth. Taken together, our results indicate that cacalol induces apoptosis in breast cancer cells and impairs mammary tumor growth in vivo by blocking the expression of the FAS gene through modulation of Akt-SREBP pathway, suggesting that cacalol has potential utility as a chemopreventive and chemotherapeutic agent for breast cancer.
authors.affiliation: Department of Medical Microbiology, Immunology & Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794-9626, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Eiji
authors.initials: E
authors.lastname: Furuta
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shindo
authors.forename: Misako
authors.initials: M
authors.lastname: Watabe
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.forename: Puspa R
authors.initials: PR
authors.lastname: Pandey
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okuda
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Pai
authors.forename: Laura L
authors.initials: LL
authors.lastname: Murphy
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
authors.forename: Aya
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Megumi
authors.initials: M
authors.lastname: Iiizumi
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.forename: Bo
authors.initials: B
authors.lastname: Xia
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D064550:Death-Associated Protein Kinases; D004357:Drug Synergism; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012717:Sesquiterpenes / Q000009:adverse effects / Q000494:pharmacology*; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D012717:Sesquiterpenes; D051779:Sterol Regulatory Element Binding Proteins; C497192:cacalol; D003520:Cyclophosphamide; D049410:Luciferases, Renilla; D064429:Fatty Acid Synthases; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; C579103:dapk2 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D053148:Caspase 3; D017239:Paclitaxel