Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells.
Numerous reports suggest that IL-6 promotes survival and proliferation of multiple myeloma (MM) cells through the phosphorylation of a cell signaling protein, STAT3. Thus, agents that suppress STAT3 phosphorylation have potential for the treatment of MM. In the present report, we demonstrate that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited IL-6-induced STAT3 phosphorylation and consequent STAT3 nuclear translocation. Curcumin had no effect on STAT5 phosphorylation, but inhibited the IFN-alpha-induced STAT1 phosphorylation. The constitutive phosphorylation of STAT3 found in certain MM cells was also abrogated by treatment with curcumin. Curcumin-induced inhibition of STAT3 phosphorylation was reversible. Compared with AG490, a well-characterized Janus kinase 2 inhibitor, curcumin was a more rapid (30 min vs 8 h) and more potent (10 micro M vs 100 micro M) inhibitor of STAT3 phosphorylation. In a similar manner, the dose of curcumin completely suppressed proliferation of MM cells; the same dose of AG490 had no effect. In contrast, a cell-permeable STAT3 inhibitor peptide that can inhibit the STAT3 phosphorylation mediated by Src blocked the constitutive phosphorylation of STAT3 and also suppressed the growth of myeloma cells. TNF-alpha and lymphotoxin also induced the proliferation of MM cells, but through a mechanism independent of STAT3 phosphorylation. In addition, dexamethasone-resistant MM cells were found to be sensitive to curcumin. Overall, our results demonstrated that curcumin was a potent inhibitor of STAT3 phosphorylation, and this plays a role in the suppression of MM proliferation.
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003474:Curcumin / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008894:Milk Proteins; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D003474:Curcumin; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D016898:Interferon-alpha; D015850:Interleukin-6; D008894:Milk Proteins; D009842:Oligopeptides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D020032:Tyrphostins; D000093242:Interleukin-6 Inhibitors; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide