Targeting PSMB2 suppresses glioblastoma progression and sensitizes tumors to temozolomide by modulating PTEN/PI3K/AKT pathway.

Abstract

Glioblastoma multiforme (GBM), a highly aggressive primary brain malignancy, is characterized by its accelerated development, refractoriness to therapy, and dismal prognosis. The proteasome subunit β2 (PSMB2), a catalytic unit of the 20S proteasome, has been linked to tumorigenesis across multiple malignancies; however, its signaling and therapeutic relevance in GBM remains incompletely defined. U87 and U251 GBM cells were engineered to overexpress (OE-PSMB2) or silence (Sh-PSMB2) PSMB2. We assessed the function of PSMB2 in GBM cell proliferation, migration, and related phenotypes, and further examined its association with the PTEN/PI3K/AKT signaling axis at both transcriptomic and protein levels. A xenograft model was conducted in the intracranial setting where the therapeutic efficacy of PSMB2 silencing, when used together with temozolomide (TMZ), was assessed. PSMB2 overexpression stimulated GBM cell proliferation, migration, and invasion, and PSMB2 silencing inhibited these phenotypes and promoted apoptosis. RNA-seq showed that PI3K/AKT pathway was enriched in Sh-PSMB2 cells. Protein-level analysis showed that PSMB2 expression was inversely associated with PTEN abundance and was accompanied by altered PI3K/AKT pathway activity. PSMB2 silencing decreased tumor burden and increased survival in vivo, and the combination of PSMB2 silencing and TMZ produced the greatest therapeutic effect. PSMB2 may function as a tumor-promoting regulator in GBM and is associated with PTEN/PI3K/AKT pathway modulation. Targeting PSMB2 suppressed tumor progression and enhanced the therapeutic response to TMZ in vivo, suggesting that PSMB2 may represent a potential therapeutic target for GBM.