Inositol hexaphosphate (IP6) is a naturally occurring phytochemical, found in abundance in cereals, legumes and other high-fiber-content diets. IP6 has shown promising efficacy against a wide range of cancers. Its anti-cancer activity involves anti-proliferative, pro-apoptotic and anti-metastatic effects. However, molecular mechanisms of its action have yet to be established. IP6 has been found to block phosphatidylinositol-3 kinase (PI3K), activating protein-1 (AP-1), protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Both matrix metalloproteinases (MMPs), a family of endopeptidases capable of degrading extracellular matrix proteins and their tissue inhibitors (TIMPs), are implicated in tumor growth, metastasis, and angiogenesis. Phorbol-12-myristate 13-acetate (PMA) is a well-known inflammatory stimulator and tumor promoter that activates PKC and increases the invasiveness of various types of cancer cells by activating MMPs.

The aim of the present study was to examine the influence of IP6 on the expression of selected MMPs, i.e., MMP-1, -2, -3, -9, 10, -13 and their TIMP-1 and -2 in unstimulated and PMA-stimulated colon cancer cell line Caco-2. Quantification of genes expression in Caco-2 cells treated with 100 ng/ml of PMA, 2.5 mM of IP6 and both for 6 and 12h was carried out using real time QRT-PCR technique. Stimulation of cells with PMA only resulted in an up-expression of MMP-3, MMP-9, MMP-10, MMP-13 and TIMP-1 mRNAs at 6 and 12h. Caco-2 revealed an increase in MMP-2 and decrease in MMP-1 genes expression after 12h of PMA treatment. The quantity of TIMP-2 transcript was reduced by PMA compared to control cells at both 6 and 12 h. A significant decrease in MMP-2, MMP-3, MMP-10, MMP-13, and TIMP-1 expression in response to 2.5 mM IP6 was observed. IP6 down-regulated MMP-9 transcription induced by PMA in 6h lasting culture and the level of both MMP-2 and MMP-3 mRNAs was increased by PMA at 12h. Caco-2 treated with both PMA and IP6 at 6 – 12h showed a significant decrease in MMP-1 expression in comparison to PMA-stimulated cells. The results of this study show that PMA, protein kinase C activator, can modulate MMP and TIMP genes transcription in colon cancer cells Caco-2. 2.5 mM IP6 exerts an influence of basal mRNA expression of some MMPs and their tissue inhibitors and down-regulates MMP-1, MMP-2, MMP-3 and MMP-9 in cells treated with PMA.

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