Loss of proliferation control is one of the major features of malignant cells. Proliferation rate is useful prognostic factor for their survival and response to treatment with anticancer drug. In proliferating cells, histone synthesis is functionally and temporally coupled with replication of DNA during the S phase. Determination of replication dependent histone H3 can be applied as a proliferative marker. Cyclin D1 (CCND1) regulates the cell cycle by participating in the control of the G1/S phase transition. IL-1 is known to act as a tumor growth factor which stimulates the proliferation and tumor cell survival. Inositol hexaphosphate (IP6), a naturally occurring phytochemical, exhibits anticancer activity in a wide range of cancers. IP6 activity has been reported to involve several processes like proliferation, apoptosis, metastasis, however, the mechanism of its anti-carcinogenic effect is still under investigation. IP6 induced cell cycle arrest in G1 phase and a significant decrease of the S phase of human cancer cells.

The aim of the present study was to examine the influence of IP6 on the expression of genes coding for proliferation markers, i.e., CCND1 and histone H3 in IL-1β-stimulated intestinal cell line Caco-2. Quantification of genes expression was carried out using real time RT-QPCR technique in Caco-2 cells after treatment with 1 ng/ml of IL-1β, 1 and 2.5 mM of IP6 for 3, 6 and 12h. In separate cultures, cells were incubated with 1 ng/ml IL-1β for the indicated times. The untreated Caco-2 cells were used as the control.

In a time course experiment, stimulation of cells with IL-1β only resulted in an overexpression of both CCND1 and histone H3 mRNAs as compared with control. IP6 had no influence on IL-1β-stimulated CCND1 expression for 3 and 6 h. After 12 h, statistically significant decrease in mRNA CCND1 was observed in cells exposed to IL-1β and IP6 (1 and 2.5 mM) in relation to cells treated with IL-1βonly. The levels of H3 mRNA in IL-1β-stimulated cells and cells treated with IL-1β and IP6 revealed no statistically significant differences after 3 h. IP6 at concentration of both 1 and 2.5 mM enhanced IL1β-stimulated transcription of H3 gene after 6 h. Subsequently (12 h), the combination of IP6 and IL-1β decreased H3 mRNA level compared to IL1β-treated cells.

In conclusion, proinflammatory cytokine IL-1β upregulates CCND1 and histone H3 mRNAs expression in colon cancer epithelial cells Caco-2. These results suggest that the ability of IP6 to inhibit colon cancer cells proliferation may be mediated through downregulation of genes encoding cyclin D1 and histone H3 at the mRNA level.

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