Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials

Trans-resveratrol, a polyphenol present in red wines and various human food s, is an antioxidant also with reported chemopreventive properties. However , whether resveratrol may exert different effects in malignant cells with a common anatomical origin yet displaying different invasive characteristics is not known. Since invasiveness and metastasis are considered to be the m ost insidious and life-threatening aspects for all cancers, we compared the ability of resveratrol to control growth and cell cycle transition in the highly invasive MDA-MB-435 with the minimally invasive MCF-7 breast carcino ma cells. The data revealed that resveratrol exerted a greater inhibitory e ffect on the MDA-MB-435 cells. A diminution of percentage of cells in G1 ph ase and a corresponding accumulation of cells in S phase of the cell cycle was observed. We also studied the effect of resveratrol on a panel of MDA-M B-435 cells transfected with nm23-H1 and nm23-H2 genes, which have been sug gested to play a role in controlling metastasis in breast cancer cells. The se cells are designated as V beta, 1 beta, 1T beta, 2 beta, and 2T beta, re spectively. The control V beta consists of MDA-MB-435 cells transfected wit h bacterial beta-glucuronidase. Cells labeled 1 beta and 1T beta correspond to those carrying B-glucuronidase and overexpressed wild-type (His118) or mutant (Tyr118, catalytically inactive) nm23-H1 genes. The 2 beta and 2T be ta refer to cells transfected with wildtype and mutant nm23-H2 genes. The r esponses of these cells to resveratrol were assessed by measuring prolifera tion, cell cycle phase distribution, and changes in expression of several g enes. These studies have shown that resveratrol (25 mu M, 3 days) reduced g rowth of all cell types by 60-80%. Overexpression of both wild-type and cat alytically inactive nm23-H1 (1 beta, 1T beta) but not nm23-H2 (2 beta, 2T b eta) reduced the proportion of cells in G1 phase, compared to the V beta co ntrol cells. Little changes in expression of PCNA, Rb, p53, and bcl-2 were observed in the five cell types treated with resveratrol, compared to untre ated cells. Noted exceptions included reduced expression of Rb protein and increased expression of p53 in 2 beta and 2T beta cells, and increased expr ession of bcl-2 in 2 beta cells, treated with resveratrol. In contrast, res veratrol upregulated expression of cathepsin D by 50-100% in all cell lines except 1 beta. These results suggest that the intrinsic metastatic potenti al of cancer cells may affect their responses to chemopreventive agents suc h as resveratrol.