Temozolomide promotes matrix metalloproteinase 9 expression through p38 MAPK and JNK pathways in glioblastoma cells

• Published in: Scientific reports Vol. 14; no. 1; pp. 14341 - 13
• Main Authors: Thanh, Hien Duong, Lee, Sueun, Nguyen, Thuy Thi, Huu, Thang Nguyen, Ahn, Eun-Jung, Cho, Sang-Hee, Kim, Min Soo, Moon, Kyung-Sub, Jung, Chaeyong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-06-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67; 631/80/86; Animals; Antineoplastic Agents, Alkylating - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; c-Fos protein; c-Jun protein; Cell Line, Tumor; Gelatinase A; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Glioma; Humanities and Social Sciences; Humans; MAP kinase; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; Mice; Molecular modelling; mRNA; multidisciplinary; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Science; Science (multidisciplinary); Temozolomide; Temozolomide - pharmacology; Transcription Factor AP-1 - metabolism; Transcription factors; Tumor cells; Tumors; Up-regulation; Up-Regulation - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-65398-2

Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of
MMP9
mRNA and
MMP9
promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.