title: Regulation of p53 and cell proliferation by resveratrol and its derivatives in breast cancer cells: an in silico and biochemical approach targeting integrin αvβ3.
abstract: Resveratrol is a grape polyphenol with cancer preventative activities in tissue culture and animal model studies. Potential of resveratrol as a broad-based chemopreventive agent have been questioned by its limited bioavailability. The bioefficacy of resveratrol was compared with its derivatives, triacetyl-resveratrol (trans-3,5,4'-triacetylstilbene) and trimethoxy-resveratrol (trans-3,5,4'-trimethoxystilbene) in both estrogen receptor-α (ERα)-positive MCF-7 and ERα-negative MDA-MB-231 breast cancer cells. Binding to integrin αvβ3 and control of cell proliferation and p53 were chosen as targets for comparative analysis using an in silico and biochemical approach. Resveratrol and triacetyl-resveratrol interacted avidly and specifically with integrin αvβ3 through binding at the site targeted by the high affinity cyclic Arg-Gly-Asp (RGD) peptide. In contrast, binding of trimethoxy-resveratrol to this site was substantially less robust. Moreover, the different stilbenes also elicited diverse cellular and signaling responses in MCF-7 and MDA-MB-231 cells, as evidenced by analysis of colony formation, cell proliferation, cell cycle phase transition, the extent of phosphorylation of p53 at Ser15 and p53-inducible proteins, p21 and p53R2, respectively. Further, stilbene-elicited signaling cascade leading to p53 activation was examined in MCF-7 cells and results showed that resveratrol and triacetyl-resveratrol induced both ERK and p38 phosphorylation, whereas only marginal changes in state of phosphorylation in these two kinases were observed in trimethoxy-resveratrol-treated cells. Taken together, these results support that resveratrol and triacetyl-resveratrol regulate proliferation and gene expression in breast cancer cells by utilizing largely similar signaling molecules and pathways and cellular events, which appear quite distinct from those targeted by trimethoxy-resveratrol.
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Tze-Chen
authors.initials: TC
authors.lastname: Hsieh
authors.forename: Christina
authors.initials: C
authors.lastname: Wong
authors.forename: Dylan
authors.initials: D
authors.lastname: John Bennett
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wu
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003198:Computer Simulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D047628:Estrogen Receptor alpha; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C047981:arginyl-glycyl-aspartic acid; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol