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.
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Authors | Jihoon 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 |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 19
Issue 24
Pg. 7582-9
(Dec 15 2011)
ISSN: 1464-3391 [Electronic] England |
PMID | 22071520
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- Anthracyclines
- Antibiotics, Antineoplastic
- STAT3 Transcription Factor
- cosmomycin C
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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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