Inhibition of Prostate Cancer Cell Colony Formation by the Flavonoid Quercetin Correlates with Modulation of Specific Regulatory Genes

Abstract

The natural product quercetin is a flavonoid found in many fruits and vegetables. Previous research has shown that quercetin has antitumor, anti-inflammatory, antiallergic, and antiviral activities. In the present investigation we studied the effect of quercetin on the ability of prostate cancer cell lines with various degrees of aggressive potential to form colonies in vitro. Specifically, we examined the molecular mechanisms underlying this effect, including the expression of cell cycle and tumor suppressor genes as well as oncogenes. We observed that quercetin at concentrations of 25 and 50 M significantly inhibited the growth of the highly aggressive PC-3 prostate cancer cell line and the moderately aggressive DU-145 prostate cancer cell line, whereas it did not affect colony formation by the poorly aggressive LNCaP prostate cancer cell line or the normal fibroblast cell line BG-9. Using the gene array methodology, we found that quercetin significantly inhibited the expression of specific oncogenes and genes controlling G 1 , S, G 2 , and M phases of the cell cycle. Moreover, quercetin reciprocally up-regulated the expression of several tumor suppressor genes. In conclusion, our results demonstrate that the antitumor effects of quercetin directly correlate with the aggressive potential of prostate cancer cells and that the mechanism(s) of quercetin-mediated antitumor effects may involve up-regulation of tumor suppressor genes and reciprocal down-regulation of oncogenes and cell cycle genes. The results of these studies provide a scientific basis for the potential use of flavonoids as nutraceuticals in the chemoprevention of cancer.The flavonoids comprise a large class of low-molecularweight, natural products of plant origin ubiquitously distributed in foods. These dietary antioxidants exert significant antitumor, antiallergic, and anti-inflammatory effects and have been extensively reviewed (14,25,38). Although various flavonoids, including quercetin, have been shown to have significant antitumor activities, the molecular mechanisms underlying these effects are generally unknown. We hypothesize that the antitumor effects of quercetin, as manifested by its ability to selectively suppress colony formation by prostate cancer cells in vitro, are mediated by its ability to regulate the expression of various genes controlling the cell cycle, tumor suppression, and oncogenesis. The present study was undertaken to investigate the effect of quercetin on the colony-forming abilities of three prostate cancer cell lines with different malignant potentials. Our results show that quercetin selectively inhibited the growth of the highly malignant PC-3 prostate cancer cell line and the moderately malignant DU-145 prostate cancer cell line but had no effect on poorly malignant LNCaP cells and normal fibroblast control cultures. MATERIALS AND METHODSCell culture. The human prostate cancer cell lines PC-3, DU-145, and LNCaP were obtained from the American Type Culture Collection (Manassas, Va.). DU-145 and PC-3 cells were isol...

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