Temozolomide promotes matrix metalloproteinase 9 expression in glioblastoma cells mainly activating p38 MAPK pathway

Chaeyong Jung

Chonnam National University. Department of Anatomy, Gwangju, South Korea

Objectives: Glioblastoma multiforme (GBM) is a highly aggressive and deadly form of brain cancer. Temozolomide (TMZ), is commonly used as a chemotherapeutic agent for GBM but a significant portion of GBM cases treated with TMZ experience recurrence and invasion of tumor cells.
Methods: We investigated whether TMZ treatment to GBM cells regulates matrix metalloproteinases (MMPs), which can promote the invasion of tumor cells. U343 and U87MG GBM cells were treated with TMZ followed by assays including western blot, reporter transcription, gelatin zymography, and in vivo assays using mouse xenograft tumors.
Results: TMZ (500M) effectively killed cells and survived cells upregulated expression of MMP9 protein. TMZ also elevated MMP9 mRNA and MMP9 promoter activity. TMZ reduced the growth of subcutaneous xenograft tumors. These tumors exhibited increased MMP9 expression. Both in vitro and in vivo studies showed TMZ-induced gelatinolytic activities of MMP9. MMP9 upregulation is mediated through the stimulation of p38 and JNK MAPK pathways leading to increased phosphorylation of p38 and JNK. This, in turn, stimulated 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 protein expression and promoter activity of MMP9 and AP-1.
Conclusion: Our data demonstrates that TMZ promoted MMP9 expression via upregulation of p38 MAPK pathway in GBM cells, suggesting that TMZ leads to the unwanted adverse effect of promoting the development of invasive cancer cells. This study also provides insights into the molecular mechanisms by which TMZ treatment may lead to increased expression of MMP9 in GBM cells, potentially promoting invasive behavior.

Keywords: MMP9; glioblastoma; matrix metalloproteinases 9; temozolomide

Ethical statement: The authors declare that there are no ethical approval required.

Funding statement: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT) (No. 2022R1A2C1003206).