A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma

Sci Rep. 2016 Oct 31;6:36132. doi: 10.1038/srep36132.

Abstract

Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Caspase 9 / metabolism
  • Cell Line
  • Cell Movement / drug effects
  • Female
  • Forkhead Box Protein O3 / metabolism
  • Harmine / therapeutic use
  • Harmine / toxicity
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Phosphorylation / drug effects
  • Phosphotyrosine / analysis
  • Phosphotyrosine / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / therapeutic use
  • Squamous Cell Carcinoma of Head and Neck
  • Tandem Mass Spectrometry
  • Tissue Array Analysis
  • Transplantation, Heterologous
  • bcl-X Protein / metabolism

Substances

  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • RNA, Small Interfering
  • Small Molecule Libraries
  • bcl-X Protein
  • Phosphotyrosine
  • Harmine
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspase 9