Mirk/Dyrk1B, a novel therapeutic target, mediates cell survival in non-small cell lung cancer cells.
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 upregulated 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.
Gao
Jingchun
J
Department of Experimental Therapeutics and Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612-9497, USA.
Zheng
Zhong
Z
Rawal
Bhupendra
B
Schell
Michael J
MJ
Bepler
Gerold
G
Haura
Eric B
EB
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000097603:Dyrk Kinases; C494772:BAK1 protein, human; C494086:STAT3 protein, human