title: Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells.
abstract: Whereas hydroxyflutamide (HF) has been used as an antiandrogen to block androgen-stimulated prostate tumor growth, the antiandrogen withdrawal syndrome that allows antiandrogens to stimulate prostate tumor growth still occurs in many patients treated with androgen ablation therapy. This was previously explained by mutations in the androgen receptor (AR) and/or modulation from AR coregulators, so that HF becomes an AR agonist. Using immunohistochemical analysis, we analyzed four prostate cancer patients undergoing androgen ablation therapy with flutamide and compared their phospho-extracellular signal-regulated kinase 1/2 levels in prostate cancer biopsies before receiving HF and after experiencing disease progression while taking HF. We found a significant increase of activated mitogen-activated protein (MAP) kinase in prostate tumors from patients receiving HF during androgen ablation therapy. In vitro studies showed that HF induced a rapid activation of the Ras/MAP kinase pathway in human prostate cancer DU145 cells which lack the AR, as well as in PC-3AR2 and CWR22 cells which express the AR. Cycloheximide failed to inhibit this activation, but both AG1478, an inhibitor of the epidermal growth factor receptor (EGF-R), and an EGF-R-neutralizing antibody blocked this HF-mediated activation of MAP kinase, which suggests that the activation of Ras/MAP kinase by HF is a membrane-initiated, non-AR-mediated, and nongenomic action. The consequence of this activation may result in increasing cell proliferation and cyclin D1 expression. This raises a concern for using HF in the complete-androgen-ablation therapy in prostate cancer treatment and provides a possible pathway that might contribute to the HF withdrawal syndrome.
authors.affiliation: George Whipple Laboratory for Cancer Research, Department of Pathology, and The Cancer Center, University of Rochester Medical Center, New York 14642, USA.
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
authors.forename: Wen-Jye
authors.initials: WJ
authors.lastname: Lin
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Edward M
authors.initials: EM
authors.lastname: Messing
authors.forename: Franky L
authors.initials: FL
authors.lastname: Chan
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019938:Cyclin D1 / Q000096:biosynthesis; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005485:Flutamide / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011799:Quinazolines; D011944:Receptors, Androgen / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000209:etiology; D020032:Tyrphostins / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D011799:Quinazolines; D011944:Receptors, Androgen; D020032:Tyrphostins; D019938:Cyclin D1; C101044:RTKI cpd; C014290:hydroxyflutamide; D005485:Flutamide; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins