期刊
CELLULAR SIGNALLING
卷 51, 期 -, 页码 222-232出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2018.08.008
关键词
Ouabain; MAP2K6; SOX9; Proliferation; Esophageal adenocarcinoma
类别
资金
- National Institutes of Health [R01DK100342, R01DK113144, R01HL132996]
- New York State Stem Cell Science [C029555]
- Price Family Foundation
- National Natural Science Foundation of China [81772994, 81302068, 81728001]
- Program for the Top Young Innovative Talents of Fujian Province [2016RCLKC]
- International Collaborative Project of Fujian Province [2017I0014]
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.
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