Withaferin A Inhibits STAT3 and Induces Tumor Cell Death in Neuroblastoma and Multiple Myeloma
| Autor: | Gabor Mocz, André S. Bachmann, Lisette P. Yco, John Opoku-Ansah |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
natural products Bioinformatics lcsh:Biochemistry chemistry.chemical_compound Neuroblastoma medicine signal transducer and activator of transcription 3 (STAT3) lcsh:QD415-436 STAT3 Withaferin A (WFA) Transcription factor Original Research biology molecular modeling business.industry General Medicine medicine.disease multiple myeloma pediatric cancer neuroblastoma chemistry Withaferin A Cancer research STAT protein biology.protein Phosphorylation business Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Biochemistry Insights Biochemistry Insights, Vol 7 (2014) Biochemistry Insights, Vol 2014, Iss 7, Pp 1-13 (2014) |
| ISSN: | 1178-6264 |
| DOI: | 10.4137/bci.s18863 |
| Popis: | Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that has been implicated in many human cancers and has emerged as an ideal target for cancer therapy. Withaferin A (WFA) is a natural product with promising antiproliferative properties through its association with a number of molecular targets including STAT3. However, the effect of WFA in pediatric neuroblastoma (NB) and its interaction with STAT3 have not been reported. In this study, we found that WFA effectively induces dose-dependent cell death in high-risk and drug-resistant NB as well as multiple myeloma (MM) tumor cells, prevented interleukin-6 (IL-6)–mediated and persistently activated STAT3 phosphorylation at Y705, and blocked the transcriptional activity of STAT3. We further provide computational models that show that WFA binds STAT3 near the Y705 phosphotyrosine residue of the STAT3 Src homology 2 (SH2) domain, suggesting that WFA prevents STAT3 dimer formation similar to BP-1-102, a well-established STAT3 inhibitor. Our findings propose that the antitumor activity of WFA is mediated at least in part through inhibition of STAT3 and provide a rationale for further drug development and clinical use in NB and MM. |
| Databáze: | OpenAIRE |
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