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Functional role of LAMC1 in modulating cuproptosis in glioma cells
Shukai Wu1, Zhigang Pan1, Jinzhong Huang1
1Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical University, 362018, China.
Abstract:
Gliomas remain highly aggressive and treatment-resistant brain tumors, necessitating novel therapeutic strategies. Recent studies have identified cuproptosis, a copper-dependent form of regulated cell death, as a potential vulnerability in cancer. However, the molecular mechanisms regulating cuproptosis in gliomas remain poorly understood. Here, we investigated the role of LAMC1 (Laminin γ1 chain), a laminin subunit implicated in glioma progression, in modulating cuproptosis sensitivity. Multi-dataset bioinformatic analysis revealed LAMC1 as a prognostic biomarker associated with copper homeostasis pathways-high LAMC1 expression correlated with poor survival and effected key cuproptosis-related genes, including FDX1 and LIAS. Functional studies showed that LAMC1 overexpression attenuates copper-induced cytotoxicity, reduces intracellular copper accumulation, and alleviates oxidative stress, whereas LAMC1 knockdown enhances cuproptosis sensitivity, increases ROS production, and disrupts redox balance. Mechanistically, LAMC1 regulates key cuproptosis effectors (FDX1, LIAS, DLAT) and copper transporters (SLC31A1, ATP7B), and modulates the PI3K/AKT signaling pathway under copper stress. The copper chelator TTM reverses the enhanced cuproptosis phenotype induced by LAMC1 knockdown, restoring cell viability and clonogenic capacity while reducing ROS and Cu2+ accumulation and normalizing cuproptosis-related gene expression. These findings establish LAMC1 as a critical regulator of cuproptosis resistance in gliomas, highlighting its potential as a therapeutic target to enhance copper-mediated cytotoxicity in glioma treatment.
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