Author/Authors :
Wang، نويسنده , , Yan and Ding، نويسنده , , Qingqing and Yen، نويسنده , , Chia-Jui and Xia، نويسنده , , Weiya and Izzo، نويسنده , , Julie G. and Lang، نويسنده , , Jing-Yu and Li، نويسنده , , Chia-Wei and Hsu، نويسنده , , Jennifer L. and Miller، نويسنده , , Stephanie A. and Wang، نويسنده , , Xuemei and Lee، نويسنده , , Dung-Fang and Hsu، نويسنده , , Jung-Mao and Huo، نويسنده , , Longfei and LaBaff، نويسنده , , Adam M. and Liu، نويسنده , , Dongping and Huang، نويسنده , , Tzu-Hsuan and Lai، نويسنده , , Chien-Chen and Tsai، نويسنده , , Fuu-Jen and Chang، نويسنده , , Wei-Chao and Chen، نويسنده , , Chung-Hsuan and Wu، نويسنده , , Tsung-Teh and Buttar، نويسنده , , Navtej S. and Wang، نويسنده , , Kenneth K. and Wu، نويسنده , , Yun and Wang، نويسنده , , Huamin and Ajani، نويسنده , , Jaffer and Hung، نويسنده , , Mien-Chie، نويسنده ,
Abstract :
Summary
geal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-α/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.
