Constitutive Activation of NF-Kb in Prostate Carcinoma Cells through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (Ikki)
Final rept. 1 Aug 2003-31 Jul 2007
NORTHWESTERN UNIV CHICAGO IL
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The overall goal of this project is to understand the role of inducible inflammation-related kinase IKKi in constitutive activation of anti-apoptotic transcription factor NF-kB prostate carcinoma PC cells. We found that IKKi is expressed in highly malignant androgen-independent PC cells lines and in epithelial cells in benign and malignant prostate lesions. Our data provide experimental evidence that IKKi could be involved in the regulation of activity of major anti-apoptotic factor NF-kB in PC cells through a positive feedback loop. Our results also suggest that IKKi may play an important role during the transition to hormone refractory stage of PC growth via its positive effect on the nuclear translocation and activity of androgen receptor in PC cells. Taking into consideration the newly recognized association between prostate inflammation and increased risk of PC development, we extended our studies towards cross-talk between pro-inflammatory signaling mediated by IKKi and NF-kB and anti-inflammatory signaling mediated by glucocorticoid receptor GR in PC cells. We showed that GR functions as a tumor suppressor in prostate cells, and that inhibition of transcription factors involved in proliferation and transformation in PC cells, including NF-kB, is the major molecular mechanism of GR anti-tumor activity. As IKKi specific inhibitors are still not available, we screened several novel classes of NF-kB inhibitors for their growth-inhibitory and anti-apoptotic effects in PC cells. The results of our studies have been presented at the local and national meetings, five manuscripts have been published, one is under revision, and two are under preparation.
- Medicine and Medical Research