Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling

The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells.

However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generated Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy.

Biochemical and biophysical research communications. 2016 Feb 24 [Epub ahead of print]

Craig Delury, Claire Hart, Mick Brown, Noel Clarke, Edward Parkin

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Genito Urinary Cancer Research Group, Institute of Cancer Sciences, Paterson Building, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4BX, UK. Genito Urinary Cancer Research Group, Institute of Cancer Sciences, Paterson Building, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4BX, UK. Genito Urinary Cancer Research Group, Institute of Cancer Sciences, Paterson Building, The University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester, M20 4BX, UK. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.