PAR2-dependent activation of GSK3{beta} regulates the survival of colon stem/progenitor cells

Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3β (GSK3β) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3β. First, PAR1 and PAR2 were identified in colon stem/progenitor cells by immunofluorescence. In three-dimensional cultures of murine crypt units or single tumor Caco-2 cells, PAR2 activation decreased numbers and size of normal or cancerous spheroids, and PAR2-deficient spheroids showed increased proliferation, indicating that PAR2 represses proliferation. PAR2-stimulated normal cells were more resistant to stress (serum starvation or spheroid passaging), suggesting prosurvival effects of PAR2. Accordingly, active caspase-3 was strongly increased in PAR2-deficient normal spheroids. PAR2 but not PAR1 triggered GSK3β activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3β activation implicates an arrestin/PP2A/GSK3β complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3β nonactive form, strengthening the role of PAR2 i...

Source: AJP: Gastrointestinal and Liver Physiology - July 31, 2016 Category: Gastroenterology Authors: Nasri, I., Bonnet, D., Zwarycz, B., d'Aldebert, E., Khou, S., Mezghani-Jarraya, R., Quaranta, M., Rolland, C., Bonnart, C., Mas, E., Ferrand, A., Cenac, N., Magness, S., Van Landeghem, L., Vergnolle, N., Racaud-Sultan, C. Tags: STEM CELLS, TISSUE ENGINEERING, DEVELOPMENT, AND CANCER Source Type: research