Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells

Oh-Joon Kwon, Joseph M. Valdez, Li Zhang, Boyu Zhang, Xing Wei, Qingtai Su, Michael M. Ittmann, Chad J. Creighton and Li Xin ()
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Oh-Joon Kwon: Baylor College of Medicine
Joseph M. Valdez: Baylor College of Medicine
Li Zhang: Baylor College of Medicine
Boyu Zhang: Baylor College of Medicine
Xing Wei: Baylor College of Medicine
Qingtai Su: Baylor College of Medicine
Michael M. Ittmann: Baylor College of Medicine
Chad J. Creighton: Dan L. Duncan Cancer Center, Baylor College of Medicine
Li Xin: Baylor College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5416

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