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Molecular Pharmacology

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Research ArticleArticle

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

Manoj K. Pandey, Bokyung Sung, Kwang Seok Ahn and Bharat B. Aggarwal
Molecular Pharmacology March 2009, 75 (3) 525-533; DOI: https://doi.org/10.1124/mol.108.052548
Manoj K. Pandey
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Bokyung Sung
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Kwang Seok Ahn
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Bharat B. Aggarwal
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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.

  • ↵ Embedded Image 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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Molecular Pharmacology: 75 (3)
Molecular Pharmacology
Vol. 75, Issue 3
1 Mar 2009
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Research ArticleArticle

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

Manoj K. Pandey, Bokyung Sung, Kwang Seok Ahn and Bharat B. Aggarwal
Molecular Pharmacology March 1, 2009, 75 (3) 525-533; DOI: https://doi.org/10.1124/mol.108.052548

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Research ArticleArticle

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

Manoj K. Pandey, Bokyung Sung, Kwang Seok Ahn and Bharat B. Aggarwal
Molecular Pharmacology March 1, 2009, 75 (3) 525-533; DOI: https://doi.org/10.1124/mol.108.052548
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