Aurora A is a negative prognostic factor and a new therapeutic target in human neuroblastoma.
We studied expression of the Aurora A gene and its clinical significance in a cohort of neuroblastoma patients. In addition, we investigated the antitumor activity of MLN8054, a novel small-molecule inhibitor of Aurora A kinase, on cultured NB cell lines in vitro. Aurora A mRNA expression was assessed by quantitative real-time PCR in tumor tissue specimens from 67 patients at diagnosis and in 9 human neuroblastoma cell lines. Western blot assays for Aurora A protein were done on tumor tissue of 53 patients. The results were correlated with various prognostic factors of neuroblastoma. Aurora A mRNA and protein expression were identified in 9 of 9 neuroblastoma cell lines. Overexpression of Aurora A mRNA in neuroblastoma tumor tissue is associated with high risk (P = 0.019), high-stage (International Neuroblastoma Staging System III and IV) tumors (P = 0.007), unfavorable histology (P = 0.007), MYCN amplification (P = 0.017), disease relapse (P = 0.019), and decreased progression-free survival (P < 0.0001) but not correlated with the age at diagnosis (P = 0.877). Similarly, Aurora A protein expression also significantly correlated with high risk (P = 0.011), high stage (P = 0.0028), unfavorable histology (P = 0.0006), MYCN amplification (P = 0.0029), and disease relapse (P = 0.044). Small interfering RNA-mediated knockdown of the endogenous Aurora A gene causes a proliferation defect and enhances chemosensitivity in human neuroblastoma cell lines. In support of these observations, the Aurora A kinase inhibitor, MLN8054, markedly inhibited growth of cultured neuroblastoma cell lines through an apoptosis-dependent pathway. Overexpression of Aurora A is associated with disease progression in neuroblastoma. Inhibition of this kinase is a promising modality for neuroblastoma treatment.
Shang
Xiaoying
X
Texas Children's Cancer Center, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Burlingame
Susan M
SM
Okcu
M Fatih
MF
Ge
Ningling
N
Russell
Heidi V
HV
Egler
Rachel A
RA
David
Rodney D
RD
Vasudevan
Sanjeev A
SA
Yang
Jianhua
J
Nuchtern
Jed G
JG
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D064127:Aurora Kinases; D001552:Benzazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D006801:Humans; D009447:Neuroblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D000970:Antineoplastic Agents; D001552:Benzazepines; C518940:MLN8054; D012333:RNA, Messenger; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases