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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.
AuthorsJihoon Kim, Yu-Jin Lee, Dae-Seop Shin, Sun-Hee Jeon, Kwang-Hee Son, Dong Cho Han, Seung-Nam Jung, Tae-Kwang Oh, Byoung-Mog Kwon
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 24 Pg. 7582-9 (Dec 15 2011) ISSN: 1464-3391 [Electronic] England
PMID22071520 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Anthracyclines
  • Antibiotics, Antineoplastic
  • STAT3 Transcription Factor
  • cosmomycin C
Topics
  • Anthracyclines (pharmacology)
  • Antibiotics, Antineoplastic (pharmacology)
  • Apoptosis (drug effects)
  • Breast Neoplasms (drug therapy, metabolism)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Female
  • Humans
  • STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
  • Signal Transduction (drug effects)
  • Streptomyces (chemistry)

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