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

Abstract

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 neurotensinmediated 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 kinased ependent activator protein-1, and extracellular signal-regulated kinase^independent nuclear factor-nB pathways. Curcumin inhibited neurotensin-mediated activator protein-1 and nuclear factor-nB 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 Amol/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)î nduced chemokine expression and cell migration.

Defining the therapeutic and preventative anti-inflammatory benefits of curcumin in vitro

“…Previously, using the human intestinal cell line (HCT116, HT-29 and CaCO 2 ), it was shown that curcumin pretreatment inhibited and modulated gene expression of IL-8 in response to inflammatory cytokine exposure 20,21 . However, it was not investigated whether curcumin had a similar effect if given simultaneously with inflammatory inducers.…”

Insulin-like growth factors are more effective than progastrin in reversing proapoptotic effects of curcumin: critical role of p38MAPK

“…Our recent findings suggest that ␤-catenin activation in response to PG is downstream of NF-B activation (45); thus activation of NF-B remains critical for measuring proliferative and antiapoptotic effects of PG. Besides PG, other gastrointestinal hormones, such as neurotensin (47) and amidated gastrins (43), also upregulate NF-B-mediated regulatory molecules such as IL-8. Thus growth-promoting and antiapoptotic effects of gastrointestinal hormones, via their cognate receptors, can be potentially mediated by the target gene products of activated NF-B pathways.…”

Molecular Mechanisms of Anti-metastatic Activity of Curcumin

“…Their results further concluded that IL-8 expression is negatively correlated to ER status and expressed preferentially in invasive cancer cells, which suggests a potential correlation between IL-8 expression and tumor progression and invasiveness. Another study also suggested that the overexpression of IL-8 associated with progression and metastasis of cancer cells in colon (37) (30). Curcumin also decreased IL-8 expression in human pancreatic cancer cell line (38).…”

“…Curcumin inhibits the activation of AP-1 in colorectal (29) and breast cancer cells (14). Wang et al reported that neurotensin increased AP-1 DNA-binding activity and curcumin inhibited the neurotensin-mediated AP-1 activation in a colon cancer cell line (30). Curcumin inhibits signal transducer and activator of transcription 3 (STAT3).…”