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Summary Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate with demonstrated anti-proliferative and anti-cancer activity in mammary cells. We hypothesized that IP6 modulates cell cycle proteins by action on cytoplasmic signaling molecules. The effects of both pharmacological (2 mM) and physiological (100 µM) doses of IP6 on major PKC isoforms (PKCa, d, e, ß and ?), PI3-K/Akt and ras/Erk1/2 were evaluated. Treatment of MCF-7 human breast cancer cells with 2 mM IP6 for 24 h caused a 3.1-fold increase in the expression of anti-proliferative PKCd. Similar results were observed with 100 µM IP6 at only 30–60 min post-treatment. IP6 also caused an increase in PKCd activity, shown by its translocation from cytosol to membrane. No changes in expression of PKC a, d, e, ß and ? were detected. Additionally, IP6 caused a decrease of Erk1/2 and Akt activity. Among cell cycle control proteins, IP6 resulted in increased p27Kip1 protein levels and marked reduction of pRb phosphorylation. Specificity of the IP6 effects on p27Kip1 and pRb in MCF-7 cells (hormone-dependent) were additionally confirmed in highly invasive hormone-independent MDA-MB 231 breast cancer cells. Use of specific pharmaclogical inhibitors of PKC d, MEK/Erk, and PI3K/Akt pathways indicated that the IP6-mediated effects on PKC d were responsible for up-regulation of p27Kip, and pRb hypo-phosphorylation. In addition, IP6-induced apoptosis detected in MCF-7 cells appeared also to be PKC d-dependent. Our data suggest potential usefulness of IP6 as a novel therapeutic modulator of PKC d and p27Kip1, an important prognostic factor in human breast cancers. [ABSTRACT FROM AUTHOR]