title: Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer.
abstract: Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21WAF1/CIP1; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer.
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.affiliation: Laboratory of Cancer Genomics, Fondazione "Edo ed Elvo Tempia Valenta", Biella, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.affiliation: Laboratory of Cancer Genomics, Fondazione "Edo ed Elvo Tempia Valenta", Biella, Italy.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Mello-Grand
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Calpini
authors.affiliation: Laboratory of Molecular Oncology, Fondazione "Edo ed Elvo Tempia Valenta", Biella, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scatolini
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy.|Internal Medicine Clinic III, Goethe University, Frankfurt am Main, Germany.
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Switzerland.|Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: G Paolo
authors.initials: GP
authors.lastname: Dotto
authors.affiliation: Laboratory of Cancer Genomics, Fondazione "Edo ed Elvo Tempia Valenta", Biella, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
mesh_terms: D000368:Aged; D063646:Carcinogenesis; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: prostate cancer; Notch