Neuropilin‐1 enhances temozolomide resistance in glioblastoma via the STAT1/p53/p21 axis

Abstract

Glioblastoma (GBM) is the most prevalent primary intracranial tumor. Temozolomide (TMZ) is the first‐line chemotherapy for GBM. Nonetheless, the development of TMZ resistance has become a main cause of treatment failure in GBM patients. Evidence suggests that neuropilin‐1 (NRP‐1) silencing can attenuate GBM cell resistance to TMZ. This study aims to determine potential mechanisms by which NRP‐1 affects TMZ resistance in GBM. The parental U251 and LN229 GBM cells were exposed to increasing concentrations of TMZ to construct TMZ‐resistant GBM cells (U251/TMZ, LN229/TMZ). BALB/c nude mice were injected with U251/TMZ cells to establish the xenograft mouse model. Functional experiments were carried out to examine NRP‐1 functions. Western blotting and real‐time quantitative polymerase chain reaction were used to evaluate molecular protein and mRNA expression, respectively. Immunohistochemical staining showed NRP‐1 and STAT1 expression in mouse tumors. The results showed that NRP‐1 was highly expressed in TMZ‐resistant cells. Moreover, knocking down NRP‐1 attenuated the TMZ resistance of U251/TMZ cells, while upregulating NRP‐1 enhanced TMZ resistance of the parental cells. NRP‐1 silencing elevated GBM cell sensitivity to TMZ in tumor‐bearing mice. Depleting NRP‐1 reduced STAT1, p53, and p21 expression in U251/TMZ cells. STAT1 depletion offset NRP‐1 silencing evoked attenuation of GBM cell resistance to TMZ. Collectively, our study reveals that NRP‐1 enhances TMZ resistance in GBM possibly by regulating the STAT1/p53/p21 axis.