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01.12.2014 | Research Paper | Ausgabe 8/2014

Clinical & Experimental Metastasis 8/2014

Capsaicin suppresses the migration of cholangiocarcinoma cells by down-regulating matrix metalloproteinase-9 expression via the AMPK–NF-κB signaling pathway

Zeitschrift:
Clinical & Experimental Metastasis > Ausgabe 8/2014
Autoren:
Gong-Rak Lee, Soo Hwa Jang, Chang Jae Kim, Ah-Ram Kim, Dong-Joon Yoon, Neung-Hwa Park, In-Seob Han
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10585-014-9678-x) contains supplementary material, which is available to authorized users.

Abstract

Cholangiocarcinoma is one of the most difficult malignancies to cure. An important prognostic factor is metastasis, which precludes curative surgical resection. Recent evidence shows that capsaicin has an inhibitory effect on cancer cell migration and invasion. Here, we investigated the molecular mechanism of the capsaicin-induced anti-migration and anti-invasion effects on HuCCT1 cholangiocarcinoma cells. Migration and invasion were significantly reduced in response to capsaicin. Capsaicin also inhibited the expression of matrix metalloproteinase-9 (MMP-9). In capsaicin-treated cells, levels of phosphorylated AMPK increased, and this effect was abolished by treatment with the AMPK inhibitor, Compound C. Capsaicin enhanced the expression of SIRT1, which can activate the transcription factor NF-κB by deacetylation. This suggests that NF-κB is activated by capsaicin via the SIRT1 pathway. In addition, capsaicin-activated AMPK induced the phosphorylation of IκBα and nuclear localization of NF-κB p65. Chromatin immunoprecipitation assays demonstrated that capsaicin reduced MMP-9 transcription by inhibiting NF-κB p65 translocation and deacetylation via SIRT1. These findings provide evidence that capsaicin suppresses the migration and invasion of cholangiocarcinoma cells by inhibiting NF-κB p65 via the AMPK–SIRT1 and the AMPK–IκBα signaling pathways, leading to subsequent suppression of MMP-9 expression.

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Zusatzmaterial
Supplementary material 1 (TIFF 24 kb) Expression of TIMP-1 and TIMP-2 (endogenous MMP-9 and MMP-2 inhibitors, respectively) is not altered in the capsaicin-treated HuCCT1 cells. Total RNA was extracted from capsaicin-treated cells and RT-PCR was performed using TIMP-1- and TIMP-2-specific primers. Cells were cultured and treated as in Fig. 2
10585_2014_9678_MOESM1_ESM.tif
Supplementary material 2 (TIFF 71 kb) Capsaicin activates SIRT1 by increasing the NAD+/NADH ratio in HuCCT1 cells. Cells were treated with Sirtinol (1 μM) or Compound C (1 μM) followed by 50 μM capsaicin for 24 h. The NAD+/NADH ratio was quantified using an NAD+/NADH Cell-Based Assay Kit (Cayman Chemical Company, MI, USA). The NAD+ and NADH concentrations were determined by colorimetric measurements at 450 nm and NAD+ standard curves. NAD+ concentration was calculated as described in the manufacturer’s manual
10585_2014_9678_MOESM2_ESM.tif
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