1. Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB
- Author
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Eulalia, Pozo-Guisado, Jaime M, Merino, Sonia, Mulero-Navarro, M Jesús, Lorenzo-Benayas, Francisco, Centeno, Alberto, Alvarez-Barrientos, Pedro M, Fernandez-Salguero, and Pedro M Fernandez, Salguero
- Subjects
Cancer Research ,Time Factors ,Apoptosis ,Membrane Potentials ,Phosphatidylinositol 3-Kinases ,Cell Movement ,Stilbenes ,Enzyme Inhibitors ,Caspase ,Caspase 8 ,biology ,Calpain ,Caspase 3 ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Cycle ,NF-kappa B ,Cytochromes c ,Flow Cytometry ,Mitochondria ,Oncology ,Matrix Metalloproteinase 9 ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,Collagen ,Signal transduction ,Poly(ADP-ribose) Polymerases ,Signal Transduction ,Programmed cell death ,Morpholines ,Immunoblotting ,Down-Regulation ,Models, Biological ,Cell Line, Tumor ,Humans ,Immunoprecipitation ,PI3K/AKT/mTOR pathway ,Nitrites ,Cell Nucleus ,Dose-Response Relationship, Drug ,Estrogens ,Antineoplastic Agents, Phytogenic ,Oxygen ,Chromones ,Resveratrol ,biology.protein ,Cancer research ,Reactive Oxygen Species - Abstract
Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERaalpha)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kappaB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kappaB, were both inhibited by RES. The patterns for NF-kappaB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kappaB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kappaB and calpain protease activity. Therefore, Bcl-2 and NF-kappaB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells.
- Published
- 2005