Butein Suppresses Constitutive and Inducible Signal Transducer and Activator of Transcription (STAT) 3 Activation and STAT3-Regulated Gene Products through the Induction of a Protein Tyrosine Phosphatase SHP-1 (original) (raw)
Research ArticleArticle
Molecular Pharmacology March 2009, 75 (3) 525-533; DOI: https://doi.org/10.1124/mol.108.052548
Abstract
The aim of the current study is to determine whether butein (3,4,2′,4′-tetrahydroxychalcone) exhibits antiproliferative effects against tumor cells through suppression of the signal transducer and activator of transcription 3 (STAT3) activation pathway. We investigated the effects of butein on constitutive and inducible STAT3 activation, role of tyrosine kinases and phosphatases in STAT3 activation, STAT3-regulated gene products, and growth modulation of tumor cells. We found that this chalcone inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells. The suppression was mediated through the inhibition of activation of the upstream kinases c-Src, Janus-like kinase (JAK) 1, and JAK2. Vanadate treatment reversed the butein-induced down-regulation of STAT3 activation, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that butein induced the expression of the tyrosine phosphatase SHP-1 and deletion of SHP-1 gene by small interfering RNA abolished the ability of butein to inhibit STAT3 activation, suggesting the critical role of SHP-1 in the action of this chalcone. Butein down-regulated the expression of STAT3-regulated gene products such as Bcl-xL, Bcl-2, cyclin D1, and Mcl-1, and this led to the suppression of proliferation and induction of apoptosis. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the butein-induced apoptosis. Moreover, we found that butein significantly potentiated the apoptotic effects of thalidomide and Velcade in MM cells. Overall, these results suggest that butein is a novel blocker of STAT3 activation and thus may have potential in suppression of tumor cell proliferation and reversal of chemoresistance in MM cells.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grants CA16672, 1P01-CA1248701] and the Clayton Foundation for Research.
ABBREVIATIONS: STAT3, signal transducer and activator of transcription 3; MM, multiple myeloma; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; PTPase, protein tyrosine phosphatase; JAK, Janus-like kinase; EGF, epithelial growth factor; IL, interleukin; siRNA, small interfering RNA; DMEM, Dulbecco's modified Eagle's medium; EMSA, electrophoretic mobility shift assay; PAGE, polyacrylamide gel electrophoresis; RT-PCR, reverse transcriptase-polymerase chain reaction; NF-κB, nuclear factor-κB; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; AG490, α-cyano-(3,4-dihydroxy)-_N_-benzylcinnamide; PD180970, pyrido[2,3-_d_]pyrimidine derivative.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.- Received October 6, 2008.
- Accepted December 22, 2008.
The American Society for Pharmacology and Experimental Therapeutics
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