Targeting Nectin-4 sensitizes glioblastoma to temozolomide.

BACKGROUND: Temozolomide (TMZ) remains the first-line chemotherapeutic agent for glioblastoma (GBM), but its clinical efficacy is often limited by acquired resistance. This study aimed to investigate whether nectin-4 could serve as a target to sensitize GBM cells to TMZ and to determine whether resveratrol enhances TMZ efficacy through downregulation of nectin-4. METHODS: Nectin-4 expression was evaluated in TMZ-treated GBM cell lines (U87, U251) and in an orthotopic GBM mouse model using qRT-PCR, Western blotting, and immunohistochemistry. Gain- and loss-of-function approaches were performed to assess the functional role of nectin-4 in GBM cell proliferation, tumor progression, and response to TMZ. The effects of resveratrol on nectin-4 expression and on the antitumor activity of TMZ were examined in vitro and in an intracranial orthotopic GBM model. RESULTS: TMZ treatment significantly upregulated nectin-4 expression at both mRNA and protein levels in GBM cells and in tumor tissues from orthotopic mouse models. Nectin-4 overexpression promoted GBM cell proliferation in vitro and accelerated intracranial tumor progression in vivo, whereas nectin-4 knockdown enhanced the antitumor activity of TMZ. Resveratrol alone effectively reduced nectin-4 expression and blocked the TMZ-induced upregulation of nectin-4. Consistent with these molecular findings, the combination of resveratrol and TMZ synergistically suppressed GBM cell proliferation, inhibited intracranial tumor growth, and significantly prolonged survival of tumor-bearing mice compared with either agent alone. CONCLUSION: Targeting nectin-4 represents an effective strategy to overcome TMZ resistance in GBM. Resveratrol enhances TMZ efficacy at least in part through downregulating nectin-4, supporting its potential as a chemo-sensitizing adjunct to TMZ-based chemotherapy for GBM patients.