Resveratrol Modulates Pro-IGF-II in MCF-7 Breast Cancer Cells

Resveratrol Modulates Pro-IGF-II in MCF-7 Breast Cancer Cells. Daisy D. De Leon and Sharda Vyas. Departments of Physiology and Anatomy, Loma Linda University, Loma Linda, CA.

Resveratrol (RSV), a phytoalexin found mainly in grapes, has been shown to function as a chemopreventive agent: it acts as an antioxidant and antimutagen (antiinitiation activity); mediates anti- inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions (anti-promotion activity); and was able to induce human promyelocytic leukemia cell differentiation (antiprogression activity). Insulin-like growth factors (IGFs) are mitogens that promote cell growth and survival in normal breast tissue as well as in breast carcinomas. Our aim was to study the effect of RSV on IGF- II at the molecular (IGF-II gene activation) and cellular (cell growth induced by IGF-II) levels in MCF-7 breast cancer cells. RSV caused a concentration-dependent (10^sup -6^ mol/L) stimulation of IGF-II mRNA in MCF-7 cells; this effect was associated with an increase of the precursor form of IGF-II (pro-IGF-II), secreted into the medium of treated cells. Further studies showed a time- and concentration-dependent increase in cell proliferation at the same RSV concentration that induced an increase in IGF-II mRNA and pro- IGF-II protein levels. To determine whether the cell proliferative effect of RSV was induced by pro-IGF-II, we performed cell growth studies after treating the cells with an anti-IGF-I receptor antibody and found a significant decrease (P < 0.05) in growth of MCF-7 cells treated simultaneously with RSV at 10~6 mol/L. Interestingly, no change in IGF-I protein levels was observed with RSV treatment, leading to the observation that pro-IGF-II was responsible for the growth stimulatory effect of RSV. Because RSV is proposed to be a chemical with potential chemopreventive use, it is noteworthy that its effects may be mediated by IGF-II, which regulates cell motility and angiogenesis, inhibits apoptosis, and increases cell proliferation. Our studies will also have clinical implications regarding characterization of the mechanism of action of RSV in breast cancer. Copyright American Institute of Nutrition Dec 2004