Abstract 5823: Uncovering the mechanisms of matrix metalloproteinase-3 (MMP-3) in the cisplatin resistance of ovarian cancer

Abstract

Abstract Seventy percent of women with ovarian cancer will develop chemotherapy-resistance to cisplatin. Regardless of the advancements in technology, mortality rates for ovarian cancer have declined only slightly in the last forty years, reiterating the need to generate novel treatment options targeting cisplatin resistance. In RNA-seq and microarrays experiments we observed that Matrix-metalloproteinase-3 (MMP3) was highly abundant in cisplatin-resistant when compared to cisplatin-sensitive cells. MMP3 is a member of the matrix metalloproteinases (MMPs) family of proteolytic enzymes, involved in the degradation of proteins in the extracellular matrix (ECM). Deregulation of MMPs alters the extracellular matrix and contributes to proliferation, invasion, and metastasis of cancerous cells. A typical MMP structure consists of a pro-domain, a catalytic, and a hemopexin domain. The catalytic domain is responsible for MMPs proteolytic activity, while the hemopexin domain contributes to substrate and ligand specificity. Inhibitors targeting the catalytic domain of MMPs were unsuccessful in clinical trials due to a lack of selectivity and specificity. When we used a chemical inhibitor, we did not observe reduced cell-proliferation or invasiveness. However, MMP3-targeted small interference RNA (siRNA) was able to reduce cell proliferation and invasive capabilities in cisplatin resistant ovarian cancer cells. Additionally, MMP3-targeted siRNA significantly reduced the sensitivity of ovarian cancer cells to cisplatin treatment. Cisplatin also increased MMP3 mRNA levels in ovarian cancer mice models and human cell lines. This evidence suggests that the MMP3 levels correlate with the sensitivity of ovarian cancer cells to cisplatin treatment. We hypothesize that the hemopexin domain will bind to proteins promoting cisplatin-resistance. We validated our expression profile studies at mRNA and protein levels via western blot, ELISA and qRT-PCR. Additionally, survival analysis using the Kaplan-Meier plotter database showed that ovarian cancer patients with low MMP3 levels live longer than patients with higher MMP3 levels. Furthermore, when we measured MMP3 activity, we observed decreased activity in cisplatin-resistant versus cisplatin-sensitive cells. Taken together, these data suggest that other domains of MMP3 (i.e., hemopexin domain) may have a function in the cisplatin resistance of ovarian cancer cells. Citation Format: Mariela Rivera-Serrano, Pablo E. Vivas-Mejia. Uncovering the mechanisms of matrix metalloproteinase-3 (MMP-3) in the cisplatin resistance of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5823.