Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state

Blood. 2010 Sep 2;116(9):1498-505. doi: 10.1182/blood-2009-11-251074. Epub 2010 Jun 2.

Abstract

Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • BALB 3T3 Cells
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic / physiology*
  • Humans
  • Immunoenzyme Techniques
  • Luciferases / metabolism
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection

Substances

  • Biomarkers, Tumor
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • RNA, Small Interfering
  • Luciferases
  • AURKA protein, human
  • AURKB protein, human
  • Aurka protein, mouse
  • Aurkb protein, mouse
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases