Abstract
Glioblastoma multiforme (GBM) is the most common form of brain tumor and is very aggressive. Rapid migration and invasion of glioblastoma cells are two typical features driving malignance of GBM. Bradykinin functionally prompts calcium influx via activation of bradykinin receptor B1/B2 (BDKRB1/2). In this study, we evaluated the roles of bradykinin in migration and invasion of glioblastoma cells and the possible mechanisms. Expressions of aquaporin 4 (AQP4) mRNA and protein were upregulated in human glioblastomas. Furthermore, exposure of human U87 MG glioblastoma cells to bradykinin specifically increased levels of BDKRB1. Successively, bradykinin stimulated influx of calcium, phosphorylation of MEK1 and extracellular signal-regulated kinase (ERK)1/2, translocation and transactivation of nuclear factor-kappaB (NF-κB), and expressions of AQP4 mRNA and protein. Concomitantly, migration and invasion of human glioblastoma cells were elevated by bradykinin. Knocking-down BDKRB1 concurrently decreased AQP4 mRNA expression and cell migration and invasion. The bradykinin-induced effects were further confirmed in murine GL261 glioblastoma cells. Therefore, bradykinin can induce AQP4 expression and subsequent migration and invasion through BDKRB1-mediated calcium influx and subsequent activation of a MEK1-ERK1/2-NF-κB pathway. The bradykinin-BDKRB1 axis and AQP4 could be precise targets for treating GBM patients.
Highlights
According to the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) in 2016, glioblastoma multiform (GBM) is a class IV neoplasm, predominantly arising from transformation of astrocytes [1]
We investigated the roles of the bradykinin-bradykinin receptor B1 (BDKRB1)/B2 axis in regulating glioblastoma cell activities and the possible mechanisms from the viewpoint of calcium influx-induced signal-transducing events in glioblastomas
Expressions of aquaporin 4 (AQP4) and BDKRB1/2 mRNAs in human glioblastoma were mined in The Cancer
Summary
According to the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) in 2016, glioblastoma multiform (GBM) is a class IV neoplasm, predominantly arising from transformation of astrocytes [1]. GBM is the most common primary brain tumor, accounting for. 16% of brain tumors in the United States [2]. GBM patients is surgical resection followed by concurrent adjuvant radiotherapy in combination with chemotherapy [3]. Temozolomide (TMZ), a DNA-alkylating agent, is the first-line chemotherapeutic drug for GBM, but most patients may develop TMZ resistance [4,5]. The poor outcomes are due to unique characteristics of glioblastoma cells, including rapid proliferation, resistance to apoptosis, and speedy migration to and invasion of surrounding healthy brain tissues [7]
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