期刊
CANCER CELL
卷 21, 期 3, 页码 374-387出版社
CELL PRESS
DOI: 10.1016/j.ccr.2011.12.028
关键词
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资金
- National Institutes of Health [CA109311, CA099031, CA16672]
- Kadoorie Charitable Foundation
- Center for Biological Pathway at the University of Texas, MD Anderson Cancer Center
- Susan G. Komen [SAC110016]
- China Medical University and Hospital
- University of Texas, MD Anderson Cancer Center
- Department of Health Cancer Research Center of Excellence, Taiwan [DOH101-TD-C-111-005, NSC100-2321-B-039-002, NSC99-2632-B-039-001-MY3]
- Dallas fund
- Park fund
- Sultan fund
- Smith fund
- Cantu Family fund
- Reivercreek foundation
- Schecter Private foundation
- Kevin and Frazier funds
- National Cancer Institute [CA142072, CA127672, CA129906]
- Multidisciplinary Research Program
Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-alpha/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of the Hedgehog (HH) pathway, has been observed in EAC. In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC.
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