Daniel E Bassi, PhD
Assistant Research Professor
Office Phone: 215-728-3155
Proprotein convertases in ovarian tumor progression
Proprotein convertases (PCs) are serine proteases that after restricted proteolysis activate many proteins that play a crucial role in cancer such as metalloproteinases, growth factors and growth factor receptors, adhesion molecules, and angiogenic factors. Although the expression of several PCs is increased in many tumors, their expression in primary ovarian tumors follows a quite distinctive pattern. We determined the association between the expression of the ubiquitously expressed PCs, furin, PACE-4, PC-5 and PC-7, and ovarian tumor progression by RT-PCR, Real-time PCR, Western blot, and immunohistochemistry using cells derived from normal human ovarian surface epithelium (HOSE) and cancer cell lines as well as ovarian epithelial cancer specimens (45 RT-PCR/Real-time PCR, and 120 archival specimens for Immunohistochemistry).
We found that furin expression was restricted to the cancer cell lines. In contrast, PACE-4 and PC-7 showed expression only in normal HOSE cells lines (figure 1). Furthermore, furin was predominantly expressed in primary tumors from patients who survived for less than five years. The other PCs are highly expressed in the group of survivors (PC-7 and PACE4) or expressed in low amounts (PC-5) (figure 2 and 3).
Our studies point to a clear relationship between furin and ovarian cancer. In addition, these results show that furin exhibits the closest association with ovarian cancer among the ubiquitously expressed PCs, arguing against the redundancy of these proteases redundancy. In summary, furin may constitute a marker for ovarian tumor progression and could contribute to predict the outcome of this disease.
Blockage of this activation step may constitute a key event in stopping tumor progression and provide further understanding on the role of the alterations of this post-translational regulatory event in cancer. Furin, a key protease in this post-translational activation, is overexpressed in ovarian cancer and in ovarian tumors with poor prognosis. In spite of this evidence associating furin with ovarian tumor progression, the effects caused by interfering with its activity and, hence, its relevance as a therapeutic target for ovarian tumor progression has not yet been addressed. In this context our long-term goal is to develop pre-clinical models of ovarian cancer based on inhibition of furin, using either protein-based as well as small molecule inhibitors.
One of the targets that contribute to tumor progression is the insulin-like growth factor receptor and the associated biological end-points for example proliferation and apoptosis, one of furin substrates. Furin blockage by either transfection or exogenous addition of PDX, antitrypsin variant Portland, a specific inhibitor of furin, resulted in decreased IGF-1R activation and proliferation, and induction of apoptosis. Furthermore, future therapies should focus in specific inhibitory effects on furin, but not PACE4 or PC-7 since the expression of these proteases was almost strictly associated to normal cell lines or in the group with better prognosis, suggesting a beneficial role for patients suffering from ovarian cancer.Top