Abstract
The overall survival for adults with malignant glioma (glioblastoma) remains poor despite advances in radiation and chemotherapy. One of the mechanisms by which cancer cells develop relative resistance to treatment is through de-regulation of endoplasmic reticulum (ER) homeostasis. We have recently shown that ABCG1, an ATP-binding cassette transporter, maintains ER homeostasis and suppresses ER stress-induced apoptosis in low-grade glioma. Herein, we demonstrate that ABCG1 expression is increased in human adult glioblastoma, where it correlates with poor survival in individuals with the mesenchymal subtype. Leveraging a mouse model of mesenchymal glioblastoma (NPcis), shRNA-mediated Abcg1 knockdown (KD) increased CHOP ER stress protein expression and resulted in greater NPcis glioma cell death in vitro. Moreover, Abcg1 KD reduced NPcis glioma growth and increased mouse survival in vivo. Collectively, these results demonstrate that ABCG1 is critical for malignant glioma cell survival, and might serve as a future therapeutic target for these deadly brain cancers.
Highlights
Brain tumors represent the fourth leading cause of cancer-related death in adults, where high-grade glial neoplasms predominate [1]
Using the one available GEO dataset containing normal reference tissue, we found that ABCG1 expression was increased in glioblastoma tumors (697 ± 554, 230913_at probe set; 428 ± 305, 232081_at probe set) relative to astrocytes (11.5 ± 1.1, 230913_at probe set; 13.9 ± 8.1, 232081_at probe set)
When the analysis was stratified by glioblastoma molecular subtype, high ABCG1 expression correlated with shorter overall survival only in the mesenchymal subgroup (Figure 1C), a subtype characterized by Neurofibromatosis type 1 (NF1) gene mutation [17]
Summary
Brain tumors represent the fourth leading cause of cancer-related death in adults, where high-grade glial neoplasms (malignant gliomas) predominate [1]. Survival following the diagnosis of a glioblastoma is dismal, with most patients dying within 12–16 months despite aggressive surgical, radiation, and chemotherapy management [1, 3] Since these cancers are thought to be maintained by cells with stem cell-like properties (glioma stem cells; GSCs), intense focus over the past decade has centered on understanding the critical pathways that govern GSC growth and differentiation [4, 5]. Most often identified by their expression of the prominin-1 cell surface marker, CD133 [6, 7], GSCs can be enriched by antibody-mediated isolation, and shown to possess unique properties such as radioresistance and chemoresistance not shared with normal brain neural stem cells (NSCs) [8,9,10] Another of these markers is the ABCG2 protein, which identifies the “side population”, a subset of stem cells hypothesized to be enriched for cancer propagation abilities [9, 11]
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