Elevated expression and secretion of TGF-α contribute to Temozolomide resistance in human glioblastoma cells

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor often treated with Temozolomide (TMZ). Research reveals that secretory substances and receptor-activated signaling may contribute to TMZ resistance in GBM cells. RNA-Seq and bioinformatics analyses reveal that TMZ treatment downregulates most genes, particularly those involved in cell structure and metabolism, while activating genes linked to secretory substances like cytokines, chemokines, and growth factors. Antibody array analysis identified a significant increase in TGF-α secretion after TMZ treatment, which also triggered its associated pathways. Moreover, the remarkable secretion of TGF-α also triggered the activation of its associated pathways. Notably, a marked increase in TGF-α expression was observed in TMZ-resistant cells. TGF-α knockdown restored TMZ sensitivity in a mouse xenograft model. Tissue analysis revealed significantly higher TGF-α levels in GBM, suggesting its potential as a drug resistance biomarker and target for new therapies.