The Aurora Kinase Inhibitor TAK901 Inhibits Glioblastoma Growth by Blocking SREBP1-Mediated Lipid Metabolism

SIMPLE SUMMARY: Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor. However, the therapeutic efficacy for GBM remains unsatisfactory. In this study, we found that TAK901, an Aurora kinase inhibitor, reduced the cell viability of both the GBM cell line and glioma stem cells (GSCs), caused cell apoptosis and considerably inhibited GBM growth in vivo. TAK901 downregulated fatty acid metabolism and cholesterol homeostasis pathways, which played an important role in GBM. Sterol regulatory element-binding protein 1 (SREBP1) overexpression alleviated the TAK901-mediated suppression of cell viability and apoptosis in GBM cells. Taken together, TAK901 is a promising therapeutic approach for GBM. ABSTRACT: Glioblastoma (GBM) is the most common and lethal malignant primary brain tumor. The standard treatment for GBM including surgical resection followed by radiation therapy and adjuvant chemotherapy with temozolomide remains unsatisfactory. In this study, we investigated the effects of the Aurora kinase inhibitor, TAK901, in GBM both in vitro and in vivo, and explored its key downstream targets. The effects of TAK901 were investigated using cell viability, cell apoptosis, live/dead, cell cycle, Transwell, 3D cell invasion, neuro-sphere, and self-renewal assays. Mechanistic studies were conducted using RNA-seq, lipid measurements, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western blotting. The in vivo efficacy of TAK901 was validated using orthotopic xenograft GBM mouse models. In both GBM cells and GSCs, TAK901 remarkably reduced cell viability, self-renewal, migration and invasion and induced apoptosis and cell cycle arrest. Treatment with TAK901 considerably inhibited GBM growth in vivo. RNA-seq and RT-qPCR analyses showed that TAK901 downregulated the expression and activation of SREBP1. Moreover, SREBP1 overexpression alleviated the TAK901-mediated suppression of cell viability and apoptosis in GBM cells. Our results provide evidence that TAK901 inhibits GBM growth by suppressing SREBP1-mediated lipid metabolism.