Overexpression of PLK1 promotes autophagy-mediated resistance to TMZ in glioblastoma cells by activating NPM1.

PURPOSE: The resistance of glioblastoma multiforme (GBM) to temozolomide (TMZ) chemotherapy poses a significant challenge in treatment. Polo-like kinase 1 (PLK1), a member of the serine/threonine protein kinase family, acts as a tumor-promoting factor in GBM cells. This study investigated the roles of PLK1 and Nucleophosmin 1 (NPM1) in GBM cell susceptibility to TMZ chemotherapy and the modulation of autophagy, exploring molecular mechanisms and signaling pathways.

METHODS

GBM cell lines with TMZ resistance were established by escalating TMZ doses. TMZ resistance was evaluated using cell counting kit-8, apoptosis, and colony formation assays in U87-MG/TMZ and SHG141/TMZ cells treated with shPLK1. Autophagy was measured by electron microscopy and western blotting. In vivo PLK1 effects were analyzed in nude mice xenografts and brain models.

RESULTS

GBM tissue exhibited higher PLK1 expression than normal tissue, correlating negatively with overall survival in patients with GBM. PLK1 increased TMZ-induced autophagy and suppressed apoptotic cell death in U87-MG/TMZ and SHG141/TMZ cells. ShPLK1 enhanced GBM cell sensitivity to TMZ, reducing TMZ-induced autophagy. PLK1 promoted autophagy by facilitating phosphorylation of serine 4 in NPM1. In vivo experiments demonstrated the ability of BI2536 to increase programmed cell death, sensitize GBM cells to TMZ therapy, and suppress autophagy by targeting NPM1 serine 4 phosphorylation.

CONCLUSIONS

PLK1 inhibition effectively suppresses autophagy, cell proliferation, TMZ resistance, and tumorigenicity, while promoting apoptosis in GBM cells through the regulation of NPM1 serine 4 phosphorylation. Targeting PLK1 presents a promising therapeutic strategy for the treatment of GBM.