Precursor insulin-like growth factor-II (proIGF-II) and mature IGF-II differentially mediate resveratrol-induced downregulation of survivin and apoptosis of MCF-7 breast cancer cells

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Insulin-like growth factor II (IGF-II) is a potent mitogen associated with cell proliferation, inhibition of apoptosis and induction of malignant transformation. Precursor IGF-II (proIGF-II) is the predominant form secreted by most tumors and is biologically active. Since resveratrol regulates IGF-II expression, we hypothesize that IGF-II mediates RSV effects on genes involved in apoptosis of breast cancer cells. This study examines whether: 1) IGF-II mediates RSV effect on survivin protein and mRNA levels; 2) proIGF-II and mature IGF-II differentially block RSV inhibition of survivin; and 3) proIGF-II and mature IGF-II differentially modulate survivin subcellular localization and mitochondrial membrane potential status. Our results show that treatment of MCF-7 cells with RSV (10^-4 M) induced a decrease of survivin protein and mRNA levels. In addition, RSV increased caspase -7 cleavage and activation. These effects were blocked by IGF-II. ProIGF-II produced a more potent effect on survivin expression and nuclear/organelle localization than mature IGF-II. MCF-7 cells transfected with proIGF-II were protected from RSV-induced apoptosis, while mIGF-II transfected cells were less protected. RSV (10^-4)did not change survivin levels in proIGF-II transfected cells.

In summary, our studies show that IGF-II mediates RSV effects on cell survival and apoptosis of MCF-7 breast cancer cells in part by regulating survivin expression.