Role of IKKs and Transcription Factor NF-kB in Prostate Tumorigenesis

Abstract

Abstract : One of the central anti-apoptotic pathways in cells is mediated by NF-kB (nuclear factor kappa-B) transcription factors. There is mounting experimental evidence that NF- kB is activated during tumorigenesis in different tissues, and that NF-kB is critically important for cell protection against apoptosis induced by different treatments including chemotherapeutic drugs and gamma-irradiation. The key to NF-kB regulation is the inhibitory kB (IkB) proteins which retain NF-kB in an inactive form in the cytoplasm. In response to diverse stimuli, IkBs are rapidly phosphorylated, ubiquitinated and undergo degradation via 26S proteasome. The released NF-kB factors then translocate to the nucleus and activate kB-responsive genes involved in cell growth, apoptosis, and metastasis. Several IkB kinases (IKKs) which trigger IkB degradation and NF-kB activation were discovered in 1997-2000 (Zandi et al., 1997, Peters and Maniatis, 2000). These protein kinases are currently seen as a target of choice to specifically inhibit NF- kB activity. In this project we proposed to test the hypothesis that activation of IKKs and down-stream NF-kB survival signaling pathway is a critical event during tumorigenesis in prostate. Our project was focused on the role of IkB kinases IKKalpha, IKKbeta, and IKKepilson (IKKepilson is called in the literature also IKKi due to its inducible nature) in constitutive activation of NF-kB in prostate carcinoma (PB) cell lines and PC tumors. We also studied whether IKK blockage induces apoptosis and/or inhibits PC cell growth. Initially I have received DOD funding for three years: from 05.01.2001 to 04.30.2004. In 2003 my laboratory moved from AMC Cancer Center in Denver to Northwestern University in Chicago. During several months of transition period in 2003 I had to rebuild my laboratory, transfer awards to NU, hire new postdoctoral fellows and technicians; prepare new IRB and IACUC protocols. I have accomplished all these goals successfully.