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Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGF(beta 1) Secretion through the AKT Signaling Pathway

Abstract : Activated pancreatic stellate cells (aPSCs), the crucial mediator of pancreatic desmoplasia, are characterized, among others, by high proliferative potential and abundant transforming growth factor (beta 1) (TGF(beta 1)) secretion. Over the past years, the involvement of Ca2+ channels in PSC pathophysiology has attracted great interest in pancreatic cancer research. We, thus, aimed to investigate the role of the Orai1 Ca2+ channel in these two PSC activation processes. Using the siRNA approach, we invalided Orai1 expression and assessed the channel functionality by Ca2+ imaging, the effect on aPSC proliferation, and TGF(beta 1) secretion. We demonstrated the functional expression of the Orai1 channel in human aPSCs and its implication in the store-operated Ca2+ entry (SOCE). Orai1 silencing led to a decrease in aPSC proliferation, TGF(beta 1) secretion, and AKT activation. Interestingly, TGF(beta 1) induced a higher SOCE response by increasing Orai1 mRNAs and proteins and promoted both AKT phosphorylation and cell proliferation, abolished by Orai1 silencing. Together, our results highlight the role of Orai1-mediated Ca2+ entry in human aPSC pathophysiology by controlling cell proliferation and TGF(beta 1) secretion through the AKT signaling pathway. Moreover, we showed a TGF(beta 1)-induced autocrine positive feedback loop by promoting the Orai1/AKT-dependent proliferation via the stimulation of Orai1 expression and function.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03607830
Contributeur : Louise Dessaivre Connectez-vous pour contacter le contributeur
Soumis le : lundi 14 mars 2022 - 11:49:10
Dernière modification le : mercredi 23 mars 2022 - 15:51:18

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Silviya Radoslavova, Antoine Folcher, Thibaut Lefebvre, Kateryna Kondratska, Stephanie Guenin, et al.. Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGF(beta 1) Secretion through the AKT Signaling Pathway. Cancers, 2021, 13 (10), ⟨10.3390/cancers13102395⟩. ⟨hal-03607830⟩

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