TY - JOUR T1 - Dihydroxypentamethoxyflavone Downregulates Constitutive and Inducible Signal Transducers and Activators of Transcription (STAT)-3 Through the Induction of Tyrosine Phosphatase SHP-1 JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.073676 SP - mol.111.073676 AU - Kanokkarn Phromnoi AU - Sahdeo Prasad AU - Subash C Gupta AU - Ramaswamy Kannappan AU - Simone Reuter AU - Pornngarm Limtrakul AU - Bharat B. Aggarwal Y1 - 2011/08/04 UR - http://molpharm.aspetjournals.org/content/early/2011/08/04/mol.111.073676.abstract N2 - Because constitutive activation of STAT3 has been linked with cellular transformation, survival, proliferation, chemoresistance, and angiogenesis of various tumor cells, agents that can suppress STAT3 activation have potential as cancer therapeutics. In the present report, we identified a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF) that has ability to inhibit STAT3 activation. PMF inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells, as indicated by suppression of STAT3 phosphorylation, nuclear translocation, DNA binding, and STAT3-regulated gene expression. The inhibition of STAT3 by PMF was reversible. We found that the activation of various kinases including Janus-activated kinase (JAK)-1, JAK-2, c-Src, ERK1/2, AKT and EGFR, implicated in STAT3 activation, were inhibited by the flavone. Interestingly, pervanadate suppressed the ability of PMF to inhibit the phosphorylation of STAT3, suggesting protein tyrosine phosphatase was involved. PMF induced the expression of SHP-1 and was linked to the dephosphorylation of STAT3, as its deletion by small interfering RNA abolished the PMF-induced constitutive as well as inducible STAT3 inhibition. STAT3 inhibition led to the suppression of proteins involved in proliferation (cyclin D1 and c-myc), survival (survivin, Mcl-1, Bcl-xL, Bcl-2 and cIAP-2), and angiogenesis (VEGF). Finally, PMF inhibited proliferation and induced apoptosis of MM cells. PMF also significantly potentiated the apoptotic effects of velcade and thalidomide in MM cells. Overall, these results suggest that PMF 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. ER -