Abstract 4406: Temozolomide-resistant glioblastoma cells promote proteolytic activities of MMPs and PAI-1 to manifest invasive potentials

Abstract Glioblastoma (GBM) is the most lethal and treatment-resistant tumor among brain cancers. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrent tumors, leading TMZ-resistant cells to evade the cytotoxic effects of TMZ and continue to invade surrounding tissues. We have recently reported that transient treatment of high-dose TMZ in GBM cells upregulates matrix metalloproteinases 9 (MMP9), resulting in increased tumor cell migration and invasion through the activation of p38 and JNK MAPK pathways. To confirm potential adverse effects caused by TMZ, in this study, we constructed TMZ-resistant GBM cells through repeated culturing of cells by gradually doubling the TMZ concentration (12.5-300 µM). TMZ-resistant cells were analyzed for proteome profiling, revealing altered expression of several proteases including MMP2/9 and PAI-1. Compared to parental cells, resistant cells showed a significant increase in migration and invasion in vitro and either inhibition of JNK or suppression of MMP9 and PAI-1 dramatically counteracted the invasive potential of resistant cells. At the same time, media collected from TMZ-resistant cells significantly activated the migration and invasion potentials of normal fibroblasts. Further mechanistic studies demonstrated that TMZ-resistant cells retain higher promoter activities of MMP9 and PAI-1 through the regulation of MAPKs and β-catenin/TCF pathways. Since resistance to TMZ in GBM tumors leads to poor treatment outcomes and low survivability for patients, results from our study about potential adverse effects from ensuing TMZ-resistant cells may contribute to these malignant processes of GBM cells. Citation Format: Hien Thanh Duong, Thang Huu Nguyen, Seongwook Jeong, Kyung-Sub Moon, Chaeyong Jung. Temozolomide-resistant glioblastoma cells promote proteolytic activities of MMPs and PAI-1 to manifest invasive potentials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4406.