Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell lines.
BACKGROUND
Medulloblastoma comprises approximately 20% of all primary pediatric brain tumors. Despite recent advances, the survival rate for high-risk patients and the morbidity associated with these treatments remains suboptimal. To improve outcomes and decrease morbidity, more targeted therapy is required. One possible target is the Aurora Kinase family. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in medulloblastoma cell lines.


METHODS
Cell proliferation was measured using an MTS assay after adding an Aurora Kinase inhibitor (C1368) at different concentrations. Cell cycle analysis was carried out by Flow Cytometry using propidium iodide (PI). RNAi experiments were performed using siRNA oligonucleotides. Luciferase experiments were carried out using the Cignal Finder 10 Pathway Reporter Arrays.


RESULTS
Inhibition of Aurora Kinase A induces cell death in medulloblastoma cells and lowers the IC(50) of other chemotherapeutic agents (etoposide and cisplatin) used in medulloblastoma treatment. Cell arrest at G2/M phase was significantly increased in medulloblastoma cell lines treated with C1368 Sigma at IC(30) or transfected siRNA. Inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways including Wnt, Myc, and RB as measured by luciferase reporter assays.


CONCLUSIONS
These data indicate that inhibition of Aurora Kinase A inhibits cell growth in medulloblastoma through inhibition of pro-proliferative signaling pathways Wnt, Myc, and RB. Additionally, combining Aurora Kinase A inhibition with other chemotherapeutic agents significantly lowers their IC(50), which make it a promising small molecule target for medulloblastoma therapy.
Department of Pediatrics, University of Iowa, Iowa, USA.
Ayman
A
El-Sheikh
Rong
R
Fan
Diane
D
Birks
Andrew
A
Donson
Nicholas K
NK
Foreman
Rajeev
R
Vibhakar
D000813:Anilides / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000813:Anilides; C550259:C 1368; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases