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.

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.

• Authors: Manoj K Pandey, Bokyung Sung, Kwang Seok Ahn, Bharat B Aggarwal
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 75 Issue 3 Pg. 525-33 (Mar 2009) ISSN: 1521-0111 [Electronic] United States
• PMID: 19103760 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Modulating Agents
• Antineoplastic Agents
• Chalcones
• STAT3 Transcription Factor
• butein
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Angiogenesis Modulating Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• Chalcones (pharmacology)
• Down-Regulation (drug effects, physiology)
• Enzyme Induction (drug effects, genetics)
• Humans
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (biosynthesis, physiology)
• STAT3 Transcription Factor (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Signal Transduction (drug effects, physiology)