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Research Paper

Mirk/Dyrk1B, a novel therapeutic target, mediates cell survival in non-small cell lung cancer cells

Jingchun Gao, Zhong Zheng, Bhupendra Rawal, Michael J. Schell, Gerold Bepler and Eric B. Haura

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Minibrain-related kinase (Mirk) is a member of the dual specificity tyrosine-
phosphorylation-regulated kinase (Dyrk)/minibrain family of dual-specificity protein
kinases and is identical to Dyrk1B. Mirk/Dyrk1B is a serine/threonine kinase that has
been found to be up-regulated in solid tumors and mediates cell survival in colon cancer,
pancreatic ductal adenocarcinoma, and rhabdomyosarcomas. There is little known about
Mirk in lung cancer. In the present study, we showed that Mirk protein was widely
overexpressed in 13 of 19 NSCLC cell lines. Mirk immunoprecipitation coupled with
anti-phosphotyrosine Western blotting confirmed tyrosine phosphorylation of Mirk in
NSCLC cells. Mirk knockdown by small interfering RNA induced cell apoptosis
concomitant with upregulation of Bak, a Bcl-2 family member, and downregulation of
signal transducers and activators of transcription 3 (STAT3) tyrosine phosphorylation.
Mirk knockdown led to decreased cell colony formation in vitro as well as delayed tumor
growth in an orthotopic mouse model and sensitized cells to cisplatin-induced apoptosis.
Using automated quantitative determination of the Mirk protein in tumor specimens of 
patients with early-stage lung cancer, overexpression of Mirk was found in nearly 90% of
tumor specimens in both the cytoplasm and nucleus. These results suggest that Mirk is
overexpressed in lung cancer, acts as a survival factor in lung cancer cells and may be a
novel therapeutic target.

Authors

Jingchun Gao

Department of Experimental Therapeutics and Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Zhong Zheng

Department of Experimental Therapeutics and Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Bhupendra Rawal

Biostatistics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Michael J. Schell

Biostatistics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Gerold Bepler

Department of Experimental Therapeutics and Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Eric B. Haura Corresponding author: Eric.Haura@moffitt.org

Department of Experimental Therapeutics and Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

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