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

揭示 MMP3 在卵巢癌顺铂耐药中的作用

基本信息

批准号：
10620830
负责人：
Pablo Elias Vivas-Mejia
金额：
$ 15万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-11 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620830
关键词：
Agreement Applications Grants Binding Biological Biomedical Research Cancer Etiology Cancer Model Cancer Patient Cancerous Catalytic Domain Cell Extracts Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Chemicals Chemoresistance Cisplatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combination Drug Therapy Conditioned Culture Media Data Disease Disease Progression Dose Enzymes Extracellular Matrix Family Genes Goals Hemopexin Immunoprecipitation Implant Intervention Investigation Knock-out Laboratories Link Liposomes Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Medical Messenger RNA Mission Molecular Molecular Biology Neoplasm Metastasis Nodule Nude Mice Pathway interactions Patients Peptide Hydrolases Platinum Play Predisposition Process Progression-Free Survivals Proliferating Proteins Proteomics Public Health Publishing Puerto Rico Quinones RNA RNA Interference Regulation Relapse Research Research Project Grants Resistance Role Science Seminal Signaling Protein Small Interfering RNA Stromelysin 1 Testing The Cancer Genome Atlas Therapeutic Therapeutic Effect Tissue-Specific Gene Expression Toxic effect Transfection Tumor Cell Invasion Tumor Weights Western Blotting Woman angiogenesis cancer cell cancer therapy carcinogenesis chemotherapy data portal design effective therapy experimental study graduate student holistic approach in vivo inhibitor intraperitoneal knock-down mouse model mutant new therapeutic target novel novel therapeutic intervention overexpression programs protein structure response subcutaneous taxane therapeutic target therapy resistant tool transcriptome sequencing trend tumor tumor growth undergraduate student university student

项目摘要

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.

摘要