Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1.
Signal transducers and activator of transcription 3 (STAT3) is a transcription factor that has been associated with survival, proliferation, chemoresistance, and angiogenesis of tumor cells. Whether the apoptotic, antiproliferative, and antimetastatic effects of guggulsterone (GS), a farnesoid X receptor antagonist, are linked to its ability to suppress STAT3 activation was investigated. We found that the Z but not the E stereoisomer of GS inhibited both constitutive and interleukin-6-induced STAT3 activation in human multiple myeloma cells. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases Janus-activated kinase 2 and c-Src. Vanadate treatment reversed the GS-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that GS induced the expression of both the protein and mRNA for tyrosine protein phosphatase SHP-1 that was not due to demethylation of the SHP-1 promoter previously implicated in the epigenetic silencing of SHP-1. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the effect of GS on induction of SHP-1 and on the inhibition of STAT3 activation, thereby implicating SHP-1 in the action of GS. Finally, GS down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of cell cycle, and induction of apoptosis. Overall, these results suggest that GS is a novel blocker of STAT3 activation and thus may have a potential in regulation of growth and metastasis of tumor cells.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kwang Seok
KS
Ahn
Gautam
G
Sethi
Bokyung
B
Sung
Ajay
A
Goel
Ranju
R
Ralhan
Bharat B
BB
Aggarwal
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004790:Enzyme Induction; D017930:Genes, Reporter; D006801:Humans; D011282:Pregnenediones / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000096:biosynthesis*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000099150:Receptor, Farnesoid X-Activated
D015342:DNA Probes; D004268:DNA-Binding Proteins; D011282:Pregnenediones; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C494086:STAT3 protein, human; C023617:pregna-4,17-diene-3,16-dione