Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells.

Abstract

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.

• Authors: Alok C Bharti, Nicholas Donato, Bharat B Aggarwal
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 171 Issue 7 Pg. 3863-71 (Oct 01 2003) ISSN: 0022-1767 [Print] United States
• PMID: 14500688 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Growth Inhibitors
• Interferon-alpha
• Interleukin-6
• Milk Proteins
• Oligopeptides
• STAT1 Transcription Factor
• STAT1 protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• STAT5 Transcription Factor
• Trans-Activators
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• Curcumin

Topics

• Active Transport, Cell Nucleus (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Membrane Permeability (drug effects)
• Cell Nucleus (drug effects, metabolism)
• Curcumin (metabolism, pharmacology)
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Growth Inhibitors (metabolism, pharmacology)
• Humans
• Interferon-alpha (antagonists & inhibitors, pharmacology)
• Interleukin-6 (antagonists & inhibitors, pharmacology)
• Milk Proteins
• Multiple Myeloma (metabolism, pathology)
• Oligopeptides (metabolism, pharmacology)
• Phosphorylation (drug effects)
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• STAT5 Transcription Factor
• Signal Transduction (drug effects)
• Trans-Activators (antagonists & inhibitors, metabolism)
• Tyrphostins (pharmacology)