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Jeon Y.J.,Korea Research Institute of Bioscience and Biotechnology | Jung S.-N.,Korea Research Institute of Bioscience and Biotechnology | Chang H.,Korea Research Institute of Bioscience and Biotechnology | Yun J.,Korea Research Institute of Bioscience and Biotechnology | And 7 more authors.
Phytotherapy Research | Year: 2015

Artocarpus altilis (Parkinson) Fosberg has traditionally been used in Indonesia for the treatment of liver cirrhosis, hypertension, and diabetes. In many other countries, it is used for the treatment of malaria, yellow fever, and dengue fever. It has been reported that A. altilis extracts have antiatherosclerotic and cytoprotective effects, but its molecular targets in tumor cells are not yet fully understood. The A. altilis extracts and the partially purified fraction have been shown to inhibit STAT3 activity and the phosphorylation of STAT3 in a dose-dependent manner. To identify the active components, a bioassay-guided isolation of the partially purified fraction resulted in the identification of a geranyl dihydrochalcone, CG901. Its chemical structure was established on the basis of spectroscopic evidence and comparison with published data. The partially purified fraction and the isolated a geranyl dihydrochalcone, CG901, down-regulated the expression of STAT3 target genes, induced apoptosis in DU145 prostate cancer cells via caspase-3 and PARP degradation, and inhibited tumor growth in human prostate tumor (DU145) xenograft initiation model. These results suggest that A. altilis could be a good natural source and that the isolated compound will be a potential lead molecule for developing novel therapeutics against STAT3-related diseases, including cancer and inflammation. Copyright © 2015 John Wiley & Sons, Ltd.


Jung S.-N.,Laboratory of Chemical Biology and Genomics | Shin D.-S.,Laboratory of Chemical Biology and Genomics | Kim H.-N.,Laboratory of Chemical Biology and Genomics | Jeon Y.J.,Laboratory of Chemical Biology and Genomics | And 9 more authors.
Biochemical Pharmacology | Year: 2015

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various human cancers and has been used as a therapeutic target for tumors. This study screened natural products to identify compounds that inhibit STAT3 activity using a STAT3-dependent luciferase reporter system. Sugiol was identified as a compound that decreased luciferase activity in a dose-dependent manner. Sugiol specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cells, and this inhibition was independent of the STAT3 upstream kinase. Sugiol induced cell cycle arrest and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, we observed that sugiol interacted with transketolase, an enzyme in central metabolism, and increased ROS levels leading to the activation of ERK, which inhibits STAT3 activity. The protein phosphatase MEG2 was also responsible for sugiol-induced STAT3 dephosphorylation. The inhibitory effect of sugiol on cell growth was confirmed using the DU145 mouse xenograft model. We propose that sugiol inhibits STAT3 activity through a mechanism that involves the inhibition of transketolase, which leads to increased ROS levels and MEG2 activation in DU145 cells. Therefore, sugiol is the first compound regulating STAT3 activity via modulation of cancer metabolic pathway and we suggest the use of sugiol as an inhibitor of the STAT3 pathway for the treatment of human solid tumors with activated STAT3. © 2015 Elsevier Inc. All rights reserved.

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