DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression

Principal Investigator: KAZANIETZ, MARCELO G
Institution Receiving Award: PENNSYLVANIA, UNIVERSITY OF
Program: PCRP
Proposal Number: PC130641
Award Number: W81XWH-14-1-0535
Funding Mechanism: Idea Development Award - Established Investigator
Partnering Awards:
Award Amount: $599,998.00


PUBLIC ABSTRACT

In this application we will investigate the role of a protein called protein kinase C epsilon (PKCepsilon) in prostate cancer. The PKC family comprises several members, some of which are known to inhibit the growth of prostate cancer cells and others, like PKCepsilon, can help prostate cancer cells to survive and proliferate faster. PKCepsilon is expressed in prostate cancer cell lines at much higher levels than in normal prostate epithelial cells, and the same has been found in clinical specimens from prostate cancer patients. However, it is not known whether PKCepsilon, when expressed in normal prostate cells, is capable of transforming them into cancerous cells, or whether it influences the action of other oncogenic and tumor suppressive alterations that commonly occur in prostate cancer. We succeeded in generating transgenic mice that overexpress PKCepsilon in the prostate (PB-PKCepsilon mice), thus recapitulating the scenario observed in human prostate tumors. Interestingly, PB-PKCepsilon mice display preneoplastic lesions in the prostate, which were classified as hyperplasia or as prostatic intraepithelial neoplastic (PIN) lesions. These lesions commonly appear in early stages of prostate cancer, therefore suggesting that PKCepsilon may play a role in the initiation of the disease. We are now in a great position to begin addressing relevant questions regarding why this happens.

Like most neoplasias, prostate cancer arises as a consequence of multiple genetic and epigenetic alterations. A well-known alteration in prostate cancer is the loss of expression of a gene called Pten. When this gene is lost or inactivated, either totally or partially, prostate epithelial cells undergo a series of changes that result ultimately in enhanced cell survival. Not surprisingly, Pten is an inhibitory ("tumor suppressor") gene, and therefore its loss can cause deleterious effects to a normal cell, as they may become more resistant to death and more susceptible to malignant transformation. A surprising result was obtained when we crossed PB-PKCepsilon mice with a mouse model that has partial (heterozygous) loss of Pten: the resulting mice displaying both alterations develop invasive prostate cancer. Thus, we could conclude that PKCepsilon overexpression and Pten loss cooperate to promote prostate cancer. We need to understand how this happens as such research may reveal mechanisms that could be hopefully targeted with pharmacological agents.

During the preliminary stages of our research, we established cellular models with and without PKCepsilon overexpression and/or Pten loss. We found that PKCepsilon-overexpressing/Pten-depleted prostate epithelial cells display uncontrolled growth and become tumorigenic and in addition they also become highly motile. Therefore, these alterations possibly play a role in promoting metastasis (the migratory process of cancer cells that actually kills prostate cancer patients). These cellular models are very important because they would allow us to explore in great detail what goes wrong in these cells and how we can fix it.

In our preliminary data, we found that PKCepsilon overexpression and Pten loss individually and synergically "turn on" the secretion of a protein called CXCL13 from prostate epithelial cells. We then carried out preliminary experiments in which we interfered with the secretion of this protein (a chemokine) from these cells, and surprisingly, we found that this affects the ability of the cells to grow and migrate. We found this result very exciting, because a pathway that may be essential for tumorigenesis and metastasis was identified. The goal now is to understand how important this pathway is in promoting prostate tumor growth and the metastatic dissemination of prostate cancer cells. We will use a range of molecular, cellular, and animal approaches to establish proof of principle that CXCL13 and its cellular receptor (known as CXCR5) could be therapeutic targets for prostate cancer. Altogether, our studies should have significant prognostic and therapeutic implications for prostate cancer and hopefully advance our understanding of the molecular basis of the disease. Most importantly, if we succeed in our endeavor, we hope to set the basis for the future development of agents targeting the PKCepsilon-CXCL13-CXCR5 pathway for the treatment of prostate cancer patients.