title: Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression.
abstract: Cellular signaling mediated by Notch receptors results in coordinated regulation of cell growth, survival, and differentiation. Aberrant Notch activation has been linked to a variety of human neoplasms. Here, we show that Notch1 signaling drives the vertical growth phase (VGP) of primary melanoma toward a more aggressive phenotype. Constitutive activation of Notch1 by ectopic expression of the Notch1 intracellular domain enables VGP primary melanoma cell lines to proliferate in a serum-independent and growth factor-independent manner in vitro and to grow more aggressively with metastatic activity in vivo. Notch1 activation also enhances tumor cell survival when cultured as three-dimensional spheroids. Such effects of Notch signaling are mediated by activation of the mitogen-activated protein kinase (MAPK) and Akt pathways. Both pathways are activated in melanoma cells following Notch1 pathway activation. Inhibition of either the MAPK or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway reverses the Notch1 signaling-induced tumor cell growth. Moreover, the growth-promoting effect of Notch1 depends on mastermind-like 1. We further showed that Notch1 activation increases tumor cell adhesion and up-regulates N-cadherin expression. Our data show regulation of MAPK/PI3K-Akt pathway activities and expression of N-cadherin by the Notch pathway and provide a mechanistic basis for Notch signaling in the promotion of primary melanoma progression.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.forename: Klara
authors.initials: K
authors.lastname: Balint
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.forename: Patricia
authors.initials: P
authors.lastname: Brafford
authors.forename: Ruihua
authors.initials: R
authors.lastname: Qiu
authors.forename: Chelsea C
authors.initials: CC
authors.lastname: Pinnix
authors.forename: Xueli
authors.initials: X
authors.lastname: Li
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular; D015534:Trans-Activators; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D004268:DNA-Binding Proteins; C430872:MAML1 protein, human; C497761:NOTCH1 protein, human; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D015534:Trans-Activators; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases