title: A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma.
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.
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605014, India.
authors: Aneesha
authors: A
authors: Radhakrishnan
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|Amrita School of Biotechnology, Amrita University, Kollam 690 525, India.
authors: Vishalakshi
authors: V
authors: Nanjappa
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.
authors: Remya
authors: R
authors: Raja
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|Manipal University, Madhav Nagar, Manipal 576104, India.
authors: Gajanan
authors: G
authors: Sathe
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|Amrita School of Biotechnology, Amrita University, Kollam 690 525, India.
authors: Vinuth N
authors: VN
authors: Puttamallesh
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors: Ankit P
authors: AP
authors: Jain
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.
authors: Sneha M
authors: SM
authors: Pinto
authors: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India.
authors: Sai A
authors: SA
authors: Balaji
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|Manipal University, Madhav Nagar, Manipal 576104, India.
authors: Sandip
authors: S
authors: Chavan
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.
authors: Nandini A
authors: NA
authors: Sahasrabuddhe
authors: Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605014, India.|School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
authors: Premendu P
authors: PP
authors: Mathur
authors: Department of Neuro-Virology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
authors: Mahesh M
authors: MM
authors: Kumar
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|Amrita School of Biotechnology, Amrita University, Kollam 690 525, India.|YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore 575018, India.
authors: T S Keshava
authors: TS
authors: Prasad
authors: Department of Pathology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
authors: Vani
authors: V
authors: Santosh
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.
authors: Geethanjali
authors: G
authors: Sukumar
authors: Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.|Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Joseph A
authors: JA
authors: Califano
authors: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India.
authors: Annapoorni
authors: A
authors: Rangarajan
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: David
authors: D
authors: Sidransky
authors: McKusick-Nathans Institute of Genetic Medicine,Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Akhilesh
authors: A
authors: Pandey
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore 575018, India.
authors: Harsha
authors: H
authors: Gowda
authors: Institute of Bioinformatics, International Technology Park, Bangalore, 560 066, India.|YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore 575018, India.
authors: Aditi
authors: A
authors: Chatterjee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D006247:Harmine / Q000627:therapeutic use / Q000633:toxicity; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000032:analysis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D054852:Small Molecule Libraries / Q000378:metabolism / Q000627:therapeutic use; D000077195:Squamous Cell Carcinoma of Head and Neck; D053719:Tandem Mass Spectrometry; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D053453:Caspase 9; D000071316:Forkhead Box Protein O3; D006247:Harmine; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D051020:bcl-X Protein; D000097603:Dyrk Kinases; C499517:FOXO3 protein, human