Prostate cancer remains the most common solid tumor in men and the second leading cause of cancer deaths among men in the United States. Although radical prostatectomy is now considered curative for localized disease, no effective treatment for metastatic prostate cancer is available. To maximize the chances for the complete cure of patients with advanced prostate cancer, it is essential to identify novel therapeutic targets for the disease. This will in the future allow the design of novel therapeutic approaches to kill or arrest the growth of prostate cancer cells while having minimal effects on non-tumor cells.
The proposed work aims at investigating the role of a protein called protein kinase C epsilon (PKCepsilon) in prostate cancer. The PKC family comprises several members. Some of the PKCs are known to inhibit the growth of prostate cancer cells and others, like PKCepsilon, can help prostate cancer cells survive and proliferate faster. PKCepsilon is unique because it is highly overexpressed in the majority of human prostate cancers. Moreover, prostate cancer aggressiveness positively correlates with PKCepsilon expression, arguing that this protein may play important roles in the progression of the disease, as well as that it may have prognostic value. Unfortunately, our knowledge on understanding of the molecular mechanisms via which PKC epsilon triggers the activation of events leading to prostate tumor development is very limited.
My studies deal with a novel connection that I have identified between PKCepsilon and the transcription factor nuclear factor kappa B (NF-kB). NF-kB regulates a number of biological processes such as cell survival, growth, cell death, and inflammation, and various studies have reported that the activity of this transcription factor is altered in prostate cancer. One well-known NF-kB-responsive gene is cyclooxygenase-2 (COX-2). Apart from its well-characterized role in inflammation, COX-2 is overexpressed in some human cancers, including prostate cancer. COX-2 has been associated with enhanced cancer cell survival, proliferation, and the ability of cancer cells to migrate and invade. As both proteins are equally altered in prostate cancer, one speculation is that they are functionally related. However, we do not have significant information on the potential functional relationship between PKCepsilon and NF-kB in prostate cancer.
Some of my initial work that I present in this application clearly suggests that PKCepsilon plays a critical role in the activation of NF-kB in different cellular models of prostate cancer. Moreover, my preliminary findings also indicate that this kinase is important for activation of NF-kB-responsive gene, particularly COX-2. In this application, I propose to investigate the underlying mechanism by which PKCepsilon mediates NF-kB activation and to determine if there is a real contribution of PKCepsilon to COX-2 activation during prostate tumorigenesis. Towards these goals, I would first use cellular and proteomics approaches to understand the mechanisms by which PKCepsilon ultimately converge on NF-kB activation. I will interfere with PKC epsilon expression or activity in prostate cancer cells and then study how this affects the expression and function of COX-2. I will also examine if overexpression of PKCepsilon in the so-called "normal" prostate RWPE1 cells or in the normal prostate epithelium of mice leads to COX-2 activation.
It has been proposed that many of the drugs that inhibit COX-2 might improve patient response to radiotherapy and hold promise in disease treatment and prevention. Therefore, I will take advantage of a specific COX-2 inhibitor to examine if pharmacological inhibition of this protein in prostate cells as well as in prostate specific PKC epsilon transgenic mice could impair PKC epsilon-driven responses, including survival, proliferation, and the development of preneoplastic and neoplastic prostate lesions.
The work that I propose may have multiple implications. In addition to gaining understanding of the underlying mechanism involved in PKCepsilon mediated NF-kB-COX2 activation and identification of PKC epsilon interacting partners, my studies may establish a strong rationale for designing drugs to treat prostate cancer patients. As PKCepsilon inhibitors are currently in preclinical studies for diseases unrelated to cancer, I strongly believe that my studies will establish proof of principle that PKCepsilon is a pharmacological target for prostate cancer therapy. Thus, I consider that my research has the potential to benefit patients in the short- or mid-term.
The training that I propose in a first class laboratory and top university will provide me with the means to gain significant experience in state-of-the-art technologies relevant for prostate cancer and may help overcoming important hurdles for treatment of prostate cancer patients. This work therefore has significant translational implications.