Regulation of IkappaB kinase epsilon expression by the androgen receptor and the nuclear factor-kappaB transcription factor in prostate cancer.
Although several genes have been associated with prostate cancer progression, it is clear that we are far from understanding all the molecular events implicated in the initiation and progression of the disease to a hormone-refractory state. The androgen receptor is a central player in the initiation and proliferation of prostate cancer and its response to hormone therapy. Nuclear factor-kappaB has important proliferative and antiapoptotic activities that could contribute to the development and progression of cancer cells as well as resistance to therapy. In this study, we report that IkappaB kinase epsilon (IKKepsilon), which is controlled by nuclear factor-kappaB in human chondrocytes, is expressed in human prostate cancer cells. We show that IKKepsilon gene expression is stimulated by tumor necrosis factor-alpha treatment in LNCaP cells and is inhibited by transfection of a dominant-negative form of IkappaBalpha, which prevents the nuclear translocation of p65. Furthermore, we found that tumor necrosis factor-alpha-induced IKKepsilon expression is inhibited by an androgen analogue (R1881) in androgen-sensitive prostate cancer cells and that this inhibition correlates with the modulation of IkappaBalpha expression by R1881. We also noted constitutive IKKepsilon expression in androgen-independent PC-3 and DU145 cells. To our knowledge, this is the first report of an IkappaB kinase family member whose expression is modulated by androgen and deregulated in androgen receptor-negative cells.
Péant
Benjamin
B
Centre de Recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montréal, Québec, Canada H2L 4M1.
Diallo
Jean-Simon
JS
Lessard
Laurent
L
Delvoye
Nathalie
N
Le Page
Cécile
C
Saad
Fred
F
Mes-Masson
Anne-Marie
AM
D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D016328:NF-kappa B / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D011944:Receptors, Androgen / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
C410798:AR protein, human; D016328:NF-kappa B; D011944:Receptors, Androgen; D015741:Metribolone; D051550:I-kappa B Kinase