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Guggulsterone, a Farnesoid X Receptor Antagonist, Inhibits Constitutive and Inducible STAT3 Activation through Induction of a Protein Tyrosine Phosphatase SHP-1

¹ Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Gastrointestinal Cancer Research Laboratory, Baylor University Medical Center, Dallas, Texas

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, Box 143, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503/713-792-6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

Key Words: Guggulsterone • STAT3 • c-Src • JAK2 • SHP-1 • Apoptosis

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-G₁ 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. [Cancer Res 2008;68(11):4406–15]