title: Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways.
abstract: Cholangiocarcinoma (CCA) is a tumor with poor prognosis that is resistant to all currently available treatments. Whether curcumin, a nutraceutical derived from turmeric (Curcuma longa), has potential therapeutic activity against human CCA was investigated using three CCA cell lines (KKU100, KKU-M156 and KKU-M213). Examination of mitochondrial dehydrogenase activity, phosphatidylserine externalization, esterase staining, caspase activation and poly-adenosine diphosphate ribose polymerase cleavage demonstrated that curcumin inhibited proliferation of and induced apoptosis in these biliary cancer cells. Colony-formation assay confirmed the growth-inhibitory effect of curcumin on CCA cells. When examined for the mechanism, curcumin was found to activate multiple cell signaling pathways in these cells. First, all CCA cells exhibited constitutively active nuclear factor (NF)-κB, and treatment with curcumin abolished this activation as indicated by DNA binding, nuclear translocation and p65 phosphorylation. Second, curcumin suppressed activation of signal transducer and activator of transcription-3 as indicated by decreased phosphorylation at both tyrosine(705) and serine(727) and inhibition of janus kinase-1 phosphorylation. Third, curcumin induced expression of peroxisome proliferator-activated receptor gamma. Fourth, curcumin upregulated death receptors, DR4 and DR5. Fifth, curcumin suppressed the Akt activation pathway. Sixth, curcumin inhibited expression of cell survival proteins such as B-cell lymphoma-2, B-cell leukemia protein xL, X-linked inhibitor of apoptosis protein, c-FLIP, cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2 and survivin and proteins linked to cell proliferation, such as cyclin D1 and c-Myc. Seventh, the growth inhibitory effect of curcumin was enhanced in the IκB kinase-deficient cells, the enzyme required for nuclear factor-kappaB activation. Overall, our results indicate that curcumin mediates its antiproliferative and apoptotic effects through activation of multiple cell signaling pathways, and thus, its activity against CCA should be further investigated.
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Suksanti
authors.initials: S
authors.lastname: Prakobwong
authors.forename: Subash C
authors.initials: SC
authors.lastname: Gupta
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.forename: Porntip
authors.initials: P
authors.lastname: Pinlaor
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Sopit
authors.initials: S
authors.lastname: Wongkham
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.forename: Somchai
authors.initials: S
authors.lastname: Pinlaor
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D047990:TNF Receptor-Associated Factor 1 / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D047495:PPAR gamma; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D047990:TNF Receptor-Associated Factor 1; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; C496559:CHUK protein, human; D051550:I-kappa B Kinase; D020169:Caspases; D003474:Curcumin