Studying the role of NF-kB in prostate cancer - an integrated approach
Vladimir Yutkin & Eli Pikarsky, Hadassah-Hebrew University Medical Centre & Hebrew University-Hadassah Medical School, Israel

Nuclear factor kappa B (NF-κB) is a collective name for a family of highly regulated proteins that regulate the expression level of other proteins (i.e. transcription factors) that are involved in several stages of cancer development in many organs. Abnormal sustained activation of NF-κB has been observed in different tumours including prostate cancer. In this project we aim to explore the role of NF-κB in prostate cancer in different stages – from its initiation (the earliest phase of cancer) till progression into its most lethal form - androgen-independent state, in which the cancer does not respond to the hormonal therapy. We will do it by using various models including primary human tumour specimens, prostate cancer cell lines and mouse models.

Our non-published results show that progression and invasive behaviour of the prostate cancer correlate well with NF-κB activity. We have demonstrated that NF-κB activation occurs more commonly in more aggressive forms of human prostate cancer, and even more so in its metastases.

We will study whether inhibition of a specific protein called β-TrCP which regulates the activity of NF-κB can be a target for developing more potent drugs to treat prostate cancer. Our preliminary studies in cell culture based model show that indeed inhibition of β-TrCP can cooperate with known treatments against prostate cancer to achieve a more pronounced effect. We will further investigate this protein (βTrCP) utilizing prostate cancer cell lines and in vivo xenograft models.

While the studies in cell lines are promising, it is only in vivo mouse models that one can directly assess the role of any specific protein or drug. We are pursuing three experimental models to study the role of NF-κB in prostate cancer development. We will test whether activation of NF-κB accelerated prostate cancer formation. This will be done in order to understand the mechanisms through which NF-κB activation can facilitate the growth and progression of prostate cancer cells. On the other hand, we will study the effect of blocking NF-κB using various genetic tools in order to assess whether NF-κB inhibition holds promises for treatment of prostate cancer patients.

In summary, we believe that this integrated approach will allow us to dissect the role of NF-κB in early and late prostate carcinogenesis and help devise therapeutic modalities that are specifically aimed at this molecule in phases were it is found to play important role.

Project commenced
June 2007

Length of project
3 years

Amount Supported
£97,440