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

• Published in: Clinical cancer research 2006-09, Vol.12 (18), p.5346-5355
• Main Authors: Wang, Xiaofu, Wang, Qingding, Ives, Kirk L, Evers, B Mark
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Calcium - metabolism; Cell Movement - drug effects; Colonic Neoplasms - secretion; curcumin; Curcumin - pharmacology; Extracellular Signal-Regulated MAP Kinases - physiology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation - drug effects; GI cancers; HCT116 Cells; Humans; IL-8; Interleukin-8 - biosynthesis; Interleukin-8 - secretion; Medical sciences; neurotensin; Neurotensin - pharmacology; NF-kappa B - physiology; Pharmacology. Drug treatments; Protein Kinase C - metabolism; signal transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription Factor AP-1 - physiology; Transcriptional Activation; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0968

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 Ca 2+ -dependent protein kinase C, extracellular signal-regulated kinase–dependent activator protein-1, and extracellular signal-regulated kinase–independent nuclear factor-κB pathways. Curcumin inhibited neurotensin-mediated activator protein-1 and nuclear factor-κB activation and Ca 2+ 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.