title: Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCdelta-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation.
abstract: 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 microM) doses of IP6 on major PKC isoforms (PKCalpha, delta, epsilon, beta and zeta), 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 PKCdelta. Similar results were observed with 100 microM IP6 at only 30-60 min post-treatment. IP6 also caused an increase in PKCdelta activity, shown by its translocation from cytosol to membrane. No changes in expression of PKC alpha, delta, epsilon, beta and zeta 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 delta, MEK/Erk, and PI3K/Akt pathways indicated that the IP6-mediated effects on PKC delta 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 delta-dependent. Our data suggest potential usefulness of IP6 as a novel therapeutic modulator of PKC delta and p27Kip1, an important prognostic factor in human breast cancers.
authors.affiliation: Department of Medical and Research Technology, University of Maryland School of Medicine, 100 Penn Street, Baltimore, MD 21201, USA ivucenik@umaryland.edu
authors.forename: Ivana
authors.initials: I
authors.lastname: Vucenik
authors.forename: Gayatri
authors.initials: G
authors.lastname: Ramakrishna
authors.forename: Kwanchanit
authors.initials: K
authors.lastname: Tantivejkul
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Anderson
authors.forename: Danica
authors.initials: D
authors.lastname: Ramljak
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000494:pharmacology*; D010766:Phosphorylation; D011379:Prognosis; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D051745:Protein Kinase C-delta; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D007295:Inositol Phosphates; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C402123:inositol heptakisphosphate; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta