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PAR2-dependent activation of GSK3? regulates the survival of colon stem/progenitor cells.

ABSTRACT: 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-3? (GSK3?) 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 GSK3?. 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 GSK3? activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3? activation implicates an arrestin/PP2A/GSK3? complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3? nonactive form, strengthening the role of PAR2 in GSK3? activation. GSK3 pharmacological inhibition impaired the survival of PAR2-stimulated spheroids and serum-starved cells. Altogether our data identify PAR2/GSK3? as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer.

SUBMITTER: Nasri I

PROVIDER: S-EPMC5007290 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells.

Nasri Imen I Bonnet Delphine D Zwarycz Bailey B d'Aldebert Emilie E Khou Sokchea S Mezghani-Jarraya Raoudha R Quaranta Muriel M Rolland Corinne C Bonnart Chrystelle C Mas Emmanuel E Ferrand Audrey A Cenac Nicolas N Magness Scott S Van Landeghem Laurianne L Vergnolle Nathalie N Racaud-Sultan Claire C

American journal of physiology. Gastrointestinal and liver physiology 20160616 2

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/proge ...[more]

PMID: 27313176

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Project description:Prenatal stress is associated with a high risk of developing adult intestinal pathologies, such as irritable bowel syndrome, chronic inflammation, and cancer. Although epithelial stem cells and progenitors have been implicated in intestinal pathophysiology, how prenatal stress could impact their functions is still unknown. We have investigated the proliferative and differentiation capacities of primitive cells using epithelial crypts isolated from colons of adult male and female mice whose mothers have been stressed during late gestation. Our results show that stem cell/progenitor proliferation and differentiation in vitro are negatively impacted by prenatal stress in male progeny. This is promoted by a reinforcement of the negative proliferative/differentiation control by the protease-activated receptor 2 (PAR2) and the muscarinic receptor 3 (M3), two G protein-coupled receptors present in the crypt. Conversely, prenatal stress does not change in vitro proliferation of colon primitive cells in female progeny. Importantly, this maintenance is associated with a functional switch in the M3 negative control of colonoid growth, becoming proliferative after prenatal stress. In addition, the proliferative role of PAR2 specific to females is maintained under prenatal stress, even though PAR2-targeted stress signals Dusp6 and activated GSK3β are increased, reaching the levels of males. An epithelial serine protease could play a critical role in the activation of the survival kinase GSK3β in colonoids from prenatally stressed female progeny. Altogether, our results show that following prenatal stress, colon primitive cells cope with stress through sexually dimorphic mechanisms that could pave the way to dysregulated crypt regeneration and intestinal pathologies.NEW & NOTEWORTHY Primitive cells isolated from mouse colon following prenatal stress and exposed to additional stress conditions such as in vitro culture, present sexually dimorphic mechanisms based on PAR2- and M3-dependent regulation of proliferation and differentiation. Whereas prenatal stress reinforces the physiological negative control exerted by PAR2 and M3 in crypts from males, in females, it induces a switch in M3- and PAR2-dependent regulation leading to a resistant and proliferative phenotype of progenitor.

Dataset Information

PAR2-dependent activation of GSK3? regulates the survival of colon stem/progenitor cells.

Publications

PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells.

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