Péant Benjamin, Diallo Jean-Simon, Lessard Laurent, Delvoye Nathalie, Le Page Cécile, Saad Fred, Mes-Masson Anne-Marie
Centre de Recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montréal, Québec, Canada H2L 4M1.
Mol Cancer Res. 2007 Jan;5(1):87-94. doi: 10.1158/1541-7786.MCR-06-0144.
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.
尽管已有多个基因与前列腺癌进展相关，但显然我们距离了解该疾病起始及进展至激素难治状态所涉及的所有分子事件仍有很大差距。雄激素受体在前列腺癌的起始、增殖及其对激素治疗的反应中起着核心作用。核因子-κB具有重要的增殖和抗凋亡活性，可能有助于癌细胞的发展和进展以及对治疗的抵抗。在本研究中，我们报告了在人软骨细胞中受核因子-κB调控的IκB激酶ε（IKKε）在人前列腺癌细胞中表达。我们发现，在LNCaP细胞中，肿瘤坏死因子-α处理可刺激IKKε基因表达，而转染一种显性负性形式的IκBα可抑制该表达，这种显性负性形式的IκBα可阻止p65的核转位。此外，我们发现，在雄激素敏感的前列腺癌细胞中，雄激素类似物（R1881）可抑制肿瘤坏死因子-α诱导的IKKε表达，且这种抑制与R1881对IκBα表达的调节相关。我们还注意到在雄激素非依赖性PC-3和DU145细胞中IKKε的组成性表达。据我们所知，这是关于IκB激酶家族成员的首次报道，其表达受雄激素调节且在雄激素受体阴性细胞中失调。
