Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas

Abstract

Aurora A is critical for mitosis and is overexpressed in several neoplasms. Its overexpression transforms cultured cells, and both its overexpression and knockdown cause genomic instability. In transgenic mice, Aurora A haploinsufficiency, not overexpression, leads to increased malignant tumor formation. Aurora A thus appears to have both tumor-promoting and tumor-suppressor functions. Here, we report that Aurora A protein, measured by quantitative protein gel blotting, is differentially expressed in major glioma types in lineage-specific patterns. Aurora A protein levels in WHO grade II oligodendrogliomas (n=16) and grade III anaplastic oligodendrogliomas (n=16) are generally low, similar to control epilepsy cerebral tissue (n=11). In contrast, pilocytic astrocytomas (n=6) and ependymomas (n=12) express high Aurora A levels. Among grade II to grade III astrocytomas (n=7, n=14, respectively) and grade IV glioblastomas (n=31), Aurora A protein increases with increasing tumor grade. We also found that Aurora A expression is induced by hypoxia in cultured glioblastoma cells and is overexpressed in hypoxic regions of glioblastoma tumors. Retrospective Kaplan-Meier analysis revealed that both lower Aurora A protein measured by quantitative protein gel blot (n=31) and Aurora A mRNA levels measured by real-time quantitative RT-PCR (n=58) are significantly associated with poorer patient survival in glioblastoma. Furthermore, we report that the selective Aurora A inhibitor MLN8237 is potently cytotoxic to glioblastoma cells, and that MLN8237 cytotoxicty is potentiated by ionizing radiation. MLN8237 also appeared to induce senescence and differentiation of glioblastoma cells. Thus, in addition to being significantly associated with survival in glioblastoma, Aurora A is a potential new drug target for the treatment of glioblastoma and possibly other glial neoplasms.

The Aurora Kinases Inhibitor VE-465 is a Novel Treatment for Glioblastoma Multiforme

“…In line with the microarray gene expression profiling analysis, positive staining for AURKA is associated with an unfavorable overall survival in medulloblastoma, which is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa [12]. In addition, AURKA is differentially expressed in gliomas and is associated with patient survival in glioblastoma [13]. These results suggest that Aurora kinases may play important roles in brain tumor process and development, and can be potential targets in GBM therapy.…”

“…Many studies have suggested that Aurora kinases may play important roles in brain tumor development and progression [12,13,16,17,18], and inhibition of Aurora-B/C can reduce malignant glioma growth in vivo [13]. This study investigated the effects of the Aurora kinase inhibitor VE-465 on GBM cell lines and explored the underlying mechanism of the antitumor effects of VE-465 on GBM cells.…”

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

“…Aurora-A overexpression may be achieved not only by gene amplification but also by other mechanisms such as transcription activation or suppression of protein degradation. Several studies, carried out on different tumors, showed that AU-RKA transcription may be induced by HIF-1a, E2F3, E4TF1, TRAP220/MED1, and c-Myc [14][15][16]. However, the mechanism of transcriptional regulation of AURKA remains largely unknown, especially in BC.…”

Radiotherapy Followed by Aurora Kinase Inhibition Targets Tumor-Propagating Cells in Human Glioblastoma

“…The small-molecule pan-AURK inhibitor VX680 is known to suppress tumor growth in animal models (32, 43). In GBM patients, expression of AURKA in tumors is associated with poor survival (44). In vitro , AURKA inhibition in GBM cell lines was cytotoxic and potentiated by ionizing radiation.…”