title: Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells.
abstract: Because signal transducer and activator of transcription 3 (STAT3) is constitutively activated in most human solid tumors and is involved in the proliferation, angiogenesis, immune evasion, and antiapoptosis of cancer cells, researchers have focused on STAT3 as a target for cancer therapy. We screened for natural compounds that inhibit the activity of STAT3 using a dual-luciferase assay. Cryptotanshinone was identified as a potent STAT3 inhibitor. Cryptotanshinone rapidly inhibited STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells and the growth of the cells through 96 hours of the treatment. Inhibition of STAT3 Tyr705 phosphorylation in DU145 cells decreased the expression of STAT3 downstream target proteins such as cyclin D1, survivin, and Bcl-xL. To investigate the cryptotanshinone inhibitory mechanism in DU145 cells, we analyzed proteins upstream of STAT3. Although phosphorylation of Janus-activated kinase (JAK) 2 was inhibited by 7 micromol/L cryptotanshinone at 24 hours, inhibition of STAT3 Tyr705 phosphorylation occurred within 30 minutes and the activity of the other proteins was not affected. These results suggest that inhibition of STAT3 phosphorylation is caused by a JAK2-independent mechanism, with suppression of JAK2 phosphorylation as a secondary effect of cryptotanshinone treatment. Continuing experiments revealed the possibility that cryptotanshinone might directly bind to STAT3 molecules. Cryptotanshinone was colocalized with STAT3 molecules in the cytoplasm and inhibited the formation of STAT3 dimers. Computational modeling showed that cryptotanshinone could bind to the SH2 domain of STAT3. These results suggest that cryptotanshinone is a potent anticancer agent targeting the activation STAT3 protein. It is the first report that cryptotanshinone has antitumor activity through the inhibition of STAT3.
authors.affiliation: Laboratory of Chemical Biology and Chemical Genomics, Korea Research Institute of Bioscience and Biotechnology, 52 Uendong Yoosunggu, Daejeon, Korea.
authors.forename: Dae-Seop
authors.initials: DS
authors.lastname: Shin
authors.forename: Hye-Nan
authors.initials: HN
authors.lastname: Kim
authors.forename: Ki Deok
authors.initials: KD
authors.lastname: Shin
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Yoon
authors.forename: Seung-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Dong Cho
authors.initials: DC
authors.lastname: Han
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019281:Dimerization; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D008958:Models, Molecular; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; D004365:Drugs, Chinese Herbal; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010616:Phenanthrenes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D051020:bcl-X Protein; D019938:Cyclin D1; C037886:cryptotanshinone; D008156:Luciferases; D011505:Protein-Tyrosine Kinases