کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8308459 | 1538493 | 2018 | 29 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Pharmacological targeting of p38 MAP-Kinase 6 (MAP2K6) inhibits the growth of esophageal adenocarcinoma
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کلمات کلیدی
CSCSox9NSGNOD SCID gammaEACHspc-Jun N-terminal kinase/stress-activated protein kinaseJNK/SAPK - JNK / SAPKEsophageal adenocarcinoma - آدنوکارسینوما مریOuabain - اوآباینProtein ANalysis THrough Evolutionary Relationships - تجزیه و تحلیل پروتئین از طریق روابط تکاملیProliferation - ترویجcancer stem cell - سلولهای بنیادی سرطانیBarrett's esophagus - مریض BarrettPANTHER - پانترHeat shock protein - پروتئین شوک حرارت
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 51, November 2018, Pages 222-232
Journal: Cellular Signalling - Volume 51, November 2018, Pages 222-232
نویسندگان
Sijie Lin, Kuancan Liu, Yongchun Zhang, Ming Jiang, Rong Lu, Christopher J. Folts, Xia Gao, Mark D. Noble, Tingting Zhao, Zhongren Zhou, Xiaopeng Lan, Jianwen Que,