title: Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells.
abstract: The prostate epithelial lineage hierarchy remains inadequately defined. Recent lineage-tracing studies have implied the existence of prostate luminal epithelial progenitors with extensive regenerative capacity. However, this capacity has not been demonstrated in prostate stem cell activity assays, probably owing to the strong susceptibility of luminal progenitors to anoikis. Here we show that constitutive expression of Notch1 intracellular domain impairs secretory function of mouse prostate luminal cells, suppresses anoikis of luminal epithelial cells by augmenting NF-κB activity independent of Hes1, stimulates luminal cell proliferation by potentiating PI3K-AKT signalling, and rescues the capacities of the putative prostate luminal progenitors for unipotent differentiation in vivo and short-term self-renewal in vitro. Epithelial cell autonomous AR signalling is dispensable for the Notch-mediated effects. As Notch activity is increased in prostate cancers, and anoikis resistance is a hallmark for metastatic cancer cells, this study suggests a pro-metastatic function of Notch signalling during prostate cancer progression.
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2].
authors.forename: Oh-Joon
authors.initials: OJ
authors.lastname: Kwon
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2].
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Valdez
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Qingtai
authors.initials: Q
authors.lastname: Su
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA [3] Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, Texas 77030, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xin
mesh_terms: D000818:Animals; D023102:Anoikis; D049109:Cell Proliferation; D002470:Cell Survival; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011467:Prostate / Q000166:cytology* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D016328:NF-kappa B; D011944:Receptors, Androgen; D051880:Receptors, Notch; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt