Unraveling the Role of MMP3 in the Cisplatin Resistance of Ovarian Cancer

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Abstract The purpose of this grant application is to promote the excellence in biomedical research of underrepresented graduate and undergraduate students of the University of Puerto Rico Medical Sciences Campus. World-wide, cancer related deaths continue to increase due to their ability to become chemotherapy resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. While the mechanism of cisplatin resistance has been extensively studied, no effective treatments have resulted, making such research critical and important. During the search for new therapeutic strategies to reverse these horrendous trends, we identified matrix metalloproteinase 3 (MMP3) to be highly abundant in cisplatin resistant ovarian cancer cells, as compared to responsive ones, using differential gene expression studies. Our seminal findings have further demonstrated that ovarian cancer tumors with high MMP3 levels relapse at a faster rate than those expressing lower levels, further supporting the notion that this enzyme plays a key role in disease progression. MMP3 belongs to the MMPs family of proteolytic enzymes that degrade multiple components of the extracellular matrix (ECM). The protein structure of MMPs includes a catalytic domain and a hemopexin (HPX) domain. Several synthetic and natural MMP inhibitors have been designed to inhibit the catalytic domain of MMPs. However, these studies were abandoned years ago due to the overt toxicities resulting from the non- specific profile of those inhibitors. However, exciting data from our laboratory seeks to reverse these disappointing trends by demonstrating that MMP3-targeting small-interfering RNAs (siRNAs) significantly reduced cell proliferation and the invasiveness ability of cisplatin resistant ovarian cancer cells. We did not observe reduced proliferation or invasiveness when we used an inhibitor that binds to the catalytic domain of the MMP3. Our preliminary results are in agreement with evidence that the HPX domain of MMP3 could binds to proteins connecting the ECM with intracellular molecular pathways. Therefore, we are poised to examine not only the contribution of MMP3 to the cisplatin resistance, but also to identify associated proteins that might contribute to this disease and they themselves represent new therapeutic targets for investigation. Therefore, we plan to test our hypothesis that other regions of MMP3 (HPX domain) interact with proteins promoting cisplatin resistance. Using a combination of molecular biology tools and our extensive and well established ovarian cancer models, we will test this central hypothesis with the following specific aims: (1) determine whether MMP3 in ovarian cancer models mediates susceptibility to the chemotherapy agent cisplatin, (2) identify the protein directly interacting with MMP3 in cisplatin resistant ovarian cancer cells, and (3) determine the biological consequences and therapeutic effects of siRNA-mediated MMP3 targeting in ovarian cancer models. Results of this research project have the potential to provide impact by enhancing understanding of therapy resistance and non-catalytic functions of MMP3 in ovarian cancer.