Tc. Hsieh et al., Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials, INT J ONCOL, 15(2), 1999, pp. 245-252
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.