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Bioorg Med Chem. 2011 Dec 15;19(24):7582-9. doi: 10.1016/j.bmc.2011.10.025. Epub 2011 Oct 17.

Cosmomycin C inhibits signal transducer and activator of transcription 3 (STAT3) pathways in MDA-MB-468 breast cancer cell.

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1
Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Yoosung, Daejeon 305-806, Republic of Korea.

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.

PMID:
22071520
DOI:
10.1016/j.bmc.2011.10.025
[Indexed for MEDLINE]
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