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Cell Signal. 2018 Nov;51:222-232. doi: 10.1016/j.cellsig.2018.08.008. Epub 2018 Aug 11.

Pharmacological targeting of p38 MAP-Kinase 6 (MAP2K6) inhibits the growth of esophageal adenocarcinoma.

Author information

1
Division of Digestive and Liver Diseases and Center for Human Development, Department of Medicine, Columbia University, NY 10032, USA; Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian 350025, PR China.
2
Division of Digestive and Liver Diseases and Center for Human Development, Department of Medicine, Columbia University, NY 10032, USA; Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian 350025, PR China; Dong fang Hospital, Xiamen University, Fuzhou, Fujian 350025, PR China. Electronic address: Liukuancan@163.com.
3
Division of Digestive and Liver Diseases and Center for Human Development, Department of Medicine, Columbia University, NY 10032, USA.
4
Department of Biomedical Genetics, University of Rochester, Rochester NY14642, USA.
5
Dong fang Hospital, Xiamen University, Fuzhou, Fujian 350025, PR China.
6
Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, MO63110, USA.
7
Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian 350025, PR China; Dong fang Hospital, Xiamen University, Fuzhou, Fujian 350025, PR China. Electronic address: Lanxp@sina.com.
8
Division of Digestive and Liver Diseases and Center for Human Development, Department of Medicine, Columbia University, NY 10032, USA. Electronic address: jq2240@cumc.columbia.edu.

Abstract

Drug repurposing with a better understanding of the underlying mechanism has provided new avenues to find treatment for malignancies. Esophageal adenocarcinoma (EAC) is a rapidly increasing cancer with a dismal 5-year survival rate of <15%. Lack of efficient treatment options contributes to the high mortality rate of EAC. To find new therapy against EAC we performed unbiased drug screening of an FDA-approved drug library and identified that the cardiac glycosides including Ouabain, Digoxin and Digitoxin efficiently inhibit the proliferation of EAC cell lines (OE33 and OE19) both in vitro and in vivo. RNA-Sequencing analysis combined with RNAi screening revealed that Ouabain suppresses the proliferation of EAC cells through downregulation of p38 MAP-Kinase 6 (MAP2K6, also known as MKK6). Consistently, shRNA-mediated knockdown of MKK6 reduced the proliferation of EAC cells and tumor growth. Further analysis demonstrated that MKK6 inhibition leads to the reduced levels of the transcription factor SOX9. In line with this finding, deletion of SOX9 with CRISPR/Cas9 resulted in decreased proliferation of EACs in 3D organoid culture and reduced tumor growth. Together these findings establish a druggable axis that can be harnessed for therapeutic gain against EAC.

KEYWORDS:

Esophageal adenocarcinoma; MAP2K6; Ouabain; Proliferation; SOX9

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