Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma.
OBJECTIVE
Aurora kinase A (AURKA) overexpression is associated with poor prognosis in neuroblastoma and has been described to upregulate VEGF in gastric cancer cells. However, the exact role of AURKA in the regulation of neuroblastoma tumorigenesis remains unknown. We hypothesize that AURKA-mediated stabilization of N-Myc may affect VEGF expression and angiogenesis in neuroblastoma. Therefore, we sought to determine whether inhibition of AURKA modulates neuroblastoma angiogenesis.


METHODS
Cell viability and anchorage-independent growth were determined after silencing AURKA or after treatment with MLN8237, AURKA inhibitor. Immunofluorescence was used to determine N-Myc localization. Human umbilical vein endothelial cells (HUVECs) were used to assess angiogenesis in vitro. Real time-PCR and ELISA were performed to determine VEGF transcription and secretion, respectively.


RESULTS
Knockdown of AURKA significantly reduced cell proliferation and inhibited anchorage-independent growth. It also decreased N-Myc protein levels and nuclear localization. AURKA inhibition also decreased HUVECs tubule formation along with VEGF transcription and secretion. Similarly, MLN8237 treatment decreased neuroblastoma tumorigenicity in vitro.


CONCLUSIONS
Our findings demonstrate that AURKA plays a critical role in neuroblastoma angiogenesis. AURKA regulates nuclear translocation of N-Myc in neuroblastoma cells, thus potentially affecting cell proliferation, anchorage-independent cell growth, and angiogenesis. Targeting AURKA might provide a novel therapeutic strategy in treating aggressive neuroblastomas.
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN.
Carmelle
C
Romain
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville TN.
Pritha
P
Paul
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN.
Kwang Woon
KW
Kim
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville TN.
Sora
S
Lee
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN.
Jingbo
J
Qiao
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville TN; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville TN. Electronic address: dai.chung@vanderbilt.edu.
Dai H
DH
Chung
D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000502:physiology; D001381:Azepines / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D009447:Neuroblastoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C576917:AURKA protein, human; D064096:Aurora Kinase A
AURKA; Angiogenesis; N-Myc; Neuroblastoma