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The NF-κB family of transcription factors is comprised of five heterodimeric members that regulates the expression of antiapoptotic genes promoting cell survival, adhesion molecules promoting cell migration and cellular interaction. It is not known how NF-κB contributes to the progression to androgen-independence and increased invasive and metastatic potential of prostate cancer (PC). Two androgen independent (AI) prostate carcinoma PC-3 and DU-145 cells have constitutive NF-κB activity, whereas LNCaP, an androgen dependent (AD) cell line does not –suggesting that this family of transcription factors is a potentially important molecular target for therapies designed to prevent PC progression. Our reporter assays demonstrate that the restoration of androgen receptor in the AI PC3 cells abrogates the constitutive activation of NF-κB in this cell line–which was not rescued by TNF-α or LPS. Adhesion and invasion assays using matrigel coated filters were used to assess the invasiveness of a highly aggressive prostate cancer cell line (PC-3), both NF-κB overexpressing and cells treated with an I kappa B adenovirus. Our initial studies have shown that PC-3 cells overexpressing NF-κB have an increased ability to adhere and invade the matrigel-coated filters. To investigate the mechanism by which NF-κB enhances the invasive and adhesive properties of PCa, we examined if overexpression of p65 in PC-3 cells will modulate bone morphogenic proteins (BMP) expression. Bone morphogenic proteins are members of the TGF-β superfamily that have been implicated in the homing of the PCa cells to the bone. We have found increased expression of BMPs 1, 4, 5, 8b and growth differentiation factor 11 transcripts in p65-overexpressing PC-3 cells compared to the control. Our immediate goal is to use neutralizing antibodies to block the BMPs and monitor the effects of the inhibition on the PCa cell adhesion and invasion to matrigel. We will also examine if the p65-induced phenotypic behavior observed in PC-3 cells will be reconstituted in AR-expressing CWR22rv1 and C4-2B cells. An in vivo system for targeted expression of a dominant negative IκB driven by the minimal enhancer elements of the probasin promoter in TRAMP mice will be established to examine the role of NF-κB in initiation, growth and progression of PC.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]