title: Cosmomycin C inhibits signal transducer and activator of transcription 3 (STAT3) pathways in MDA-MB-468 breast cancer cell.
abstract: The signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells. Therefore, blocking the aberrant activity of STAT3 in tumor cells is a validated therapeutic strategy. To discover novel inhibitors of STAT3 activity, we screened against microbial natural products using a dual-luciferase assay. Using the microbial metabolome library, we identified cosmomycin C (CosC), which was isolated from the mycelium extract of Streptomyces sp. KCTC19769, as a STAT3 pathway inhibitor. CosC inhibited STAT3 (Tyr705) phosphorylation and subsequent nuclear translocation in MDA-MB-468 breast cancer cells. CosC-mediated inhibition of STAT3 signaling pathway was confirmed by suppressed expression of STAT3 downstream target proteins including cyclin D1, Bcl-xL, survivin, Mcl-1, and VEGF in CosC-treated MDA-MB-468 cells. Flow cytometry showed that CosC caused accumulation in the G(0)-G(1) phase of the cell cycle and induced apoptosis via PARP cleavage and caspase-3 activation. Based on these findings, CosC may be a potential candidate for modulation of STAT3 pathway.
authors.affiliation: Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Yoosung, Daejeon 305-806, Republic of Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Kim
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Dae-Seop
authors.initials: DS
authors.lastname: Shin
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Jeon
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Son
authors.forename: Dong Cho
authors.initials: DC
authors.lastname: Han
authors.forename: Seung-Nam
authors.initials: SN
authors.lastname: Jung
authors.forename: Tae-Kwang
authors.initials: TK
authors.lastname: Oh
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013302:Streptomyces / Q000737:chemistry
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D050796:STAT3 Transcription Factor; C053964:cosmomycin C