title: The crosstalk of mTOR/S6K1 and Hedgehog pathways.
abstract: Esophageal 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.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Julie G
authors.initials: JG
authors.lastname: Izzo
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Lang
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Li
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Miller
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.forename: Longfei
authors.initials: L
authors.lastname: Huo
authors.forename: Adam M
authors.initials: AM
authors.lastname: Labaff
authors.forename: Dongping
authors.initials: D
authors.lastname: Liu
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Huang
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Navtej S
authors.initials: NS
authors.lastname: Buttar
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Jaffer
authors.initials: J
authors.lastname: Ajani
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048049:Extracellular Signal-Regulated MAP Kinases