NF‐κB activation in human prostate cancer: Important mediator or epiphenomenon?

The NF‐κB family of transcription factors has been shown to be constitutively activated in various human malignancies, including leukemias, lymphomas, and a number of solid tumors. NF‐κB is hypothesized to contribute to development and/or progression of malignancy by regulating the expression of genes involved in cell growth and proliferation, anti‐apoptosis, angiogenesis, and metastasis. Prostate cancer cells have been reported to have constitutive NF‐κB activity due to increased activity of the IκB kinase complex. Furthermore, an inverse correlation between androgen receptor (AR) status and NF‐κB activity was observed in prostate cancer cell lines. NF‐κB may promote cell growth and proliferation in prostate cancer cells by regulating expression of genes such as c‐myc , cyclin D1, and IL‐6. NF‐κB may also inhibit apoptosis in prostate cancer cells through activation of expression of anti‐apoptotic genes, such as Bcl‐2 , although pro‐apoptotic activity of NF‐κB has also been reported. NF‐κB‐mediated expression of genes involved in angiogenesis (IL‐8, VEGF), and invasion and metastasis (MMP9, uPA, uPA receptor) may further contribute to the progression of prostate cancer. Constitutive NF‐κB activity has also been demonstrated in primary prostate cancer tissue samples and suggested to have prognostic importance for a subset of primary tumors. The limited number of samples analyzed in those studies and the relative lack of NF‐κB target genes identified in RNA expression microarray analyses of prostate cancer cells suggest that further studies will be required in order to determine if NF‐κB actually plays a role in human prostate cancer development, and/or progression, and to characterize its potential as a therapeutic target. © 2003 Wiley‐Liss, Inc.