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Cell surface GRP78 as a biomarker and target for suppressing glioma cells.

ABSTRACT: High-grade glioma is a highly malignant and metastatic brain cancer, resistant to many existing anticancer treatments. In such glioma cancer cells, the glucose-regulated protein 78?kDa (GRP78) is particularly highly up-regulated. Former studies have thus targeted mutation-free GRP78 not only to detect glioma cancer cells specifically but also to enhance cytotoxic effect. We focus on cell surface-expressed GRP78 as a target for suppressing high-grade glioma cell lines. Glioblastoma multiforme (GBM) cell line, highly malignant glioma cells, was first injected into 5-week-old athymic mice to confirm and compare GRP78 expression in vivo in xenografted and normal brain tissue. Immunofluorescence and immunoblotting were utilized to detect surface-localized GRP78 in diverse high-grade glioma cell lines. By treating glioma cell lines with the polyclonal N-20 antibody against surface-localized GRP78, we subsequently studied the significance of surface GRP78 to the survival and growth of the glioma cell lines. We found that inhibiting the function of surface GRP78 suppressed cancer cell survival and growth proving that the surface-expressed GRP78 is a vital receptor involved in the proliferation of high-grade glioma. Our findings provide opportunities to target surface GRP78 as a biomarker for high-grade glioma and to develop effective cell-specific anticancer therapy.

SUBMITTER: Kang BR

PROVIDER: S-EPMC5054676 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Cell surface GRP78 as a biomarker and target for suppressing glioma cells.

Kang Bo Ram BR Yang Seung-Hoon SH Chung Bo-Ryehn BR Kim Woong W Kim YoungSoo Y

Scientific reports 20161007

High-grade glioma is a highly malignant and metastatic brain cancer, resistant to many existing anticancer treatments. In such glioma cancer cells, the glucose-regulated protein 78 kDa (GRP78) is particularly highly up-regulated. Former studies have thus targeted mutation-free GRP78 not only to detect glioma cancer cells specifically but also to enhance cytotoxic effect. We focus on cell surface-expressed GRP78 as a target for suppressing high-grade glioma cell lines. Glioblastoma multiforme (GB ...[more]

PMID: 27713511

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Project description:BackgroundGlioma stem cells (GSCs) are considered the initial cells of gliomas, contributing to therapeutic resistance. Patient-derived GSCs well recapitulate the heterogeneity of their parent glioma tissues, which can be classified into different subtypes. Likewise, previous works identified GSCs as two distinct subtypes, mesenchymal (MES) and proneural (PN) subtypes, and with general recognition, the MES subtype is considered a more malignant phenotype characterized by high invasion and radioresistance. Therefore, understanding the mechanisms involved in the MES phenotype is necessary for glioblastoma treatment.MethodsData for bioinformatic analysis were obtained from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database. An antibody was used to block cell surface glucose-regulated protein 78 (csGRP78). Apoptosis and cell cycle analyses were performed to evaluate radiation damage. Immunofluorescence staining was applied to assess protein expression and distribution. Mass spectrometry combined with bioinformatic analysis was used to screen downstream molecules. Intracranial GSC-derived xenografts were established for in vivo experiments.ResultsTotal GRP78 expression was associated with MES GSC stemness, and csGRP78 was highly expressed in MES GSCs. Targeting csGRP78 suppressed the self-renewal and radioresistance of MES GSCs in vitro and in vivo, accompanied by downregulation of the STAT3, NF-κB and C/EBPβ pathways. Mass spectrometry revealed the potential downstream β-site APP-cleaving enzyme 2 (BACE2), which was regulated by csGRP78 via lysosomal degradation. Knockdown of BACE2 inactivated NF-κB and C/EBPβ and significantly suppressed the tumorigenesis and radioresistance of MES GSCs in vitro and in vivo.ConclusionsCell surface GRP78 was preferentially expressed in MES GSCs and played a pivotal role in MES phenotype maintenance. Thus, blocking csGRP78 in MES GSCs with a high-specificity antibody might be a promising novel therapeutic strategy.

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Cell surface GRP78 as a biomarker and target for suppressing glioma cells.

Publications

Cell surface GRP78 as a biomarker and target for suppressing glioma cells.

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