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Curcumin Inhibits Neurotensin-Mediated Interleukin-8 Production and Migration of HCT116 Human Colon Cancer Cells

Authors' Affiliations: ¹ Department of Surgery and ² The Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas

Requests for reprints: B. Mark Evers, Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0536. Phone: 409-772-5254; Fax: 409-747-4819; E-mail: mevers{at}utmb.edu.

Purpose: Neurotensin, a gut tridecapeptide, acts as a potent cellular mitogen for various colorectal and pancreatic cancers that possess high-affinity neurotensin receptors. Cytokine/chemokine proteins are increasingly recognized as important local factors that play a role in the metastasis and invasion of multiple cancers. The purpose of this study was to (a) determine the effect of neurotensin on cytokine/chemokine gene expression and cell migration in human cancer cells and (b) assess the effect of curcumin, a natural dietary product, on neurotensin-mediated processes.

Experimental Design: The human colorectal cancer, HCT116, was treated with neurotensin, with or without curcumin, and interleukin (IL)-8 expression and protein secretion was measured. Signaling pathways, which contribute to the effects of neurotensin, were assessed. Finally, the effect of curcumin on neurotensin-mediated HCT116 cell migration was analyzed.

Results: We show that neurotensin, acting through the native high-affinity neurotensin receptor, induced IL-8 expression in human colorectal cancer cells in a time- and dose-dependent fashion. This stimulation involves Ca²⁺-dependent protein kinase C, extracellular signal-regulated kinase–dependent activator protein-1, and extracellular signal-regulated kinase–independent nuclear factor-B pathways. Curcumin inhibited neurotensin-mediated activator protein-1 and nuclear factor-B activation and Ca²⁺ mobilization. Moreover, curcumin blocked neurotensin-stimulated IL-8 gene induction and protein secretion and, at a low concentration (i.e., 10 µmol/L), blocked neurotensin-stimulated colon cancer cell migration.

Conclusions: Neurotensin-mediated induction of tumor cell IL-8 expression and secretion may contribute to the procarcinogenic effects of neurotensin on gastrointestinal cancers. Furthermore, a potential mechanism for the chemopreventive and chemotherapeutic effects of curcumin on colon cancers may be through the inhibition of gastrointestinal hormone (e.g., neurotensin)–induced chemokine expression and cell migration.

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