Inhibition of ErbB-2 and ErbB-3 expression by quercetin prevents transforming growth factor alpha (TGF-alpha)- and epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell proliferation.
Because ErbB-2 receptor is involved in hormone-independency for growth and metastasis of prostate cancer cells, the aim was to investigate the effects of quercetin on ErbB-2 and ErbB-3 expression and its critical components such as MAP kinase and PI-3 kinase. Hemocytometric counts and [3H]-thymidine incorporation were used to determine the effects of quercetin, EGF and TGF-alpha on cell proliferation and DNA synthesis in PC-3 and LnCap cells. Changes in ErbB-2, ErbB-3 and components of MAPK and PI-3K pathways were analyzed by Western blot analysis. Treatment of PC-3 and LnCap cells with quercetin resulted in a dose-dependent growth inhibition. The rate of DNA synthesis was decreased by 40, 55 and 65% on treatment with 14.5, 29.0 and 58.0 microM of quercetin, respectively. Concomitantly, these treatments led to a dose-dependent decrease in ErbB-2, ErbB-3 and their basal autophosphorylation levels as compared to controls. Cyclin D1 expression and basal phosphorylation of c-Raf, MAPK, Elk-1 and Akt-1 in PC-3 cells was also inhibited by quercetin treatment. Co-treating PC-3 cells with quercetin significantly attenuated EGF- and TGF-alpha-induced growth and phosphorylation of ErbB-2, ErbB-3, c-Raf, MAPK kinase 1/2 (MEK1/2), MAPK, Elk-1 and Akt-1. Since ErbB receptor is important for growth, metastasis and drug resistance, inhibition of ErbB-2 and ErbB-3 by pharmacological doses of quercetin may provide a new approach for treatment of prostate cancers.
Huynh
Hung
H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610, Republic of Singapore. cmrhth@nccs.com.sg
Nguyen
Thi Thanh Tuyen
TT
Chan
Eli
E
Tran
Evelyne
E
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000378:metabolism*
D019938:Cyclin D1; D004247:DNA; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019908:Proto-Oncogene Proteins c-raf; D011794:Quercetin; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D016211:Transforming Growth Factor alpha