The Crosstalk of mTOR/S6K1 and Hedgehog Pathways

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• 作者：Yan Wang¹ ; Qingqing Ding¹ ; Chia-Jui Yen¹ ; Weiya Xia¹ ; Julie  ; G. Izzo² ; ³ ; Jing-Yu Lang¹ ; Chia-Wei Li¹ ; Jennifer  ; L. Hsu¹ ; ⁸ ; ¹⁴ ; Stephanie  ; A. Miller¹ ; Xuemei Wang⁴ ; Dung-Fang Lee¹ ; ⁹ ; Jung-Mao Hsu¹ ; ⁹ ; Longfei Huo¹ ; Adam  ; M. LaBaff¹ ; ⁹ ; Dongping Liu¹ ; Tzu-Hsuan Huang¹ ; Chien-Chen Lai⁷ ; ¹⁰ ; Fuu-Jen Tsai⁶ ; Wei-Chao Chang⁸ ; ¹¹ ; Chung-Hsuan Chen¹¹ ; Tsung-Teh Wu¹² ; Navtej  ; S. Buttar¹³ ; Kenneth  ; K. Wang¹³ ; Yun Wu⁵ ; Huamin Wang⁵ ; Jaffer Ajani³ ; Mien-Chie Hung¹ ; ⁸ ; ⁹ ; ¹⁴ ; ^{mhung@mdanderson.org}
• 刊名：Cancer Cell
• 出版年：2012
• 出版时间：20 March, 2012
• 年：2012
• 卷：21
• 期：3
• 页码：374-387
• 全文大小：2822 K

文摘

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Summary

Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-¦Á/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.