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Signaling pathways mediating manganese-induced toxicity in human glioblastoma cells (u87)
Shilpa Puli1, James C K Lai, Kristina L Edgley
1Department of Pharmaceutical Sciences, College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID 83209, USA.
Abstract:
Although essential, manganese (Mn) intake in excess leads to neurotoxicity. Mn neurotoxicity induces impairment of energy metabolism and ultimately cell death. Nevertheless, the signaling mechanisms underlying Mn toxicity are unknown. Employing human glioblastoma (U87) cells, we investigated several signaling pathways (ones promoting cellular proliferation and invasion) underlying Mn toxicity. Mn-treatment of U87 cells induced a down-regulation of MAPK pathway but the AKT pathway was not markedly affected. Mn-treatment of these cells induced decreases in their levels of c-Jun and c-Fos transcription factors and extracellular matrix degrading enzymes like MMP-2, which are associated with glioblastoma invasiveness. Mn-treatment also induced apoptosis in U87 cells. Thus, our results indicate that other than inducing apoptosis in U87 cells, Mn exerts differential effects on several signaling pathways promoting glioblastoma proliferation and invasion. Consequently, Mn may have pathophysiological roles in inducing apoptosis and in blocking glioblastoma invasion. Our results may thus have therapeutic implications.
Insights
Excess manganese (Mn) causes neurotoxicity by impairing energy metabolism and inducing cell death. This study reveals Mn's effects on glioblastoma cell signaling, potentially impacting invasion and apoptosis.
Area of Science:
- Neurotoxicology
- Cellular Signaling
- Cancer Biology
Background:
- Manganese (Mn) is essential but toxic in excess, causing neurotoxicity through impaired energy metabolism and cell death.
- The precise signaling mechanisms behind Mn neurotoxicity remain largely unknown.
- Glioblastoma multiforme is an aggressive brain tumor characterized by proliferation and invasion.
Purpose of the Study:
- To investigate the signaling pathways affected by Mn toxicity in human glioblastoma (U87) cells.
- To elucidate the role of Mn in glioblastoma cell proliferation, invasion, and apoptosis.
- To explore potential therapeutic implications of Mn's effects on glioblastoma.
Main Methods:
- Human glioblastoma (U87) cells were treated with manganese (Mn).
- Investigated the mitogen-activated protein kinase (MAPK) and AKT signaling pathways.
- Assessed levels of transcription factors c-Jun and c-Fos, and matrix metalloproteinase-2 (MMP-2).
- Evaluated Mn-induced apoptosis using U87 cells.
Main Results:
- Mn treatment down-regulated the MAPK pathway but did not significantly affect the AKT pathway.
- Mn exposure decreased levels of c-Jun, c-Fos, and MMP-2, key factors in glioblastoma invasion.
- Mn-induced apoptosis was observed in U87 cells.
- Mn demonstrated differential effects on signaling pathways regulating glioblastoma proliferation and invasion.
Conclusions:
- Manganese induces apoptosis in glioblastoma cells.
- Mn may inhibit glioblastoma invasion by down-regulating specific signaling pathways and matrix-degrading enzymes.
- These findings suggest Mn could have therapeutic potential in managing glioblastoma.
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