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.