The expression and regulation of proliferation-linked genes in cancer

Cancer is a disease characterized by altered regulation of cell growth and proliferation. Studies were conducted which examined the expression and regulation of different proliferation-linked genes in non-transformed and transformed cells. These genes included the matrix metalloproteinases (MMPs), which mediate metastasis, survivin, which is an inhibitor of apoptosis protein (IAP), and ornithine decarboxylase (ODC) and spermidine/spermine N 1-acetyltransferase (SSAT), both of which are integral in polyamine metabolism. The effects of flavonoid-enriched fractions from lowbush blueberry (Vaccinium angustifolium) on MMP regulation was examined in DU 145 human prostate cancer cells. It was shown that MMP-2 and MMP-9 were down-regulated by lowbush blueberry fractions, and that this regulation was protein kinase C (PKC) and/or mitogen activated protein (MAP) kinase dependent. Survivin expression in 10T½ and NR3 cells was examined in response to the mitogenic growth factors, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). Survivin expression was induced in NR3 cells by all growth factors, and results show that survivin induction by each growth factor was phoshatidylinositol-3 (PI3) kinase dependent, while PDGF and EGF also used competent PKC and MAP kinase pathways to induce survivin. The expression of ODC and SSAT in 10T½ and NR3 cells was examined in response to insulin-like growth factor (IGF)-1 and -2. Results show that IGF-1 and IGF-2 induce both ODC and SSAT, and that both IGF-1- and IGF-2-mediated induction of these enzymes was PKC and MAP kinase dependent. These results illustrate the complex regulation of important proliferation-linked genes in cancer cells, and may provide further insight into the mechanisms involved in the selective growth advantage observed in cancer cells.