Doublecortin-Like Kinase: A Potential Therapeutic Target for Neuroblastoma

Publication Type:

Journal Article

Source:

Neuro-Oncology, Volume 14, Number Suppl. 3, p.91-91 (2012)

ISBN:

1522-8517

DOI Name (links to online publication)

10.1093/neuonc/nos183

Abstract:

Doublecortin-like kinase (DCLK) gene encodes microtubule-associated proteins that are crucial for correct proliferation and differentiation of neuroprogenitor cells.Gene expression profiling revealed a high expression of DCLK transcripts in neuroblastomas (NBs).These transcripts are endogenously expressed in neuroblasts but are not found in other cell types.Suppression of DCLK by short interfering RNA (siRNA) disrupted themitotic spindles in NB cells and gene expression profiling revealed numerous differentially expressed genes indicating apoptosis.Apoptotic cell death of NB cells by DCLK knockdown was further confirmed by several assays.Interestingly, mitochondria were the most affected cell components after DCLK knockdown.In human NBs a highly significant correlation between DCLK expression and genes related with mitochondria activity was detected.In fact, we found that DCLK is crucial for cytochrome c oxidase activity and ATP synthesis in NB cells.Furthermore, DCLK silencing in NB xenograft models in mice resulted in a significant delay in NB tumor growth.Less proliferation and more apoptotic cells were detected in NB tumors with DCLK knockdown than in tumors expressing DCLK.In summary, 1) DCLK is crucial for proliferation and survival of NB cells and 2) in vivo studies showed that NB tumors with DCLK knockdown have a growth delay.Therefore, our results strongly indicate that DCLK is a potential therapeutic target for NB.

18/01/2013