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Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGF_β1 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 _β1 (TGF_β1) 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_β1 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_β1 secretion, and AKT activation. Interestingly, TGF_β1 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_β1 secretion through the AKT signaling pathway. Moreover, we showed a TGF_β1-induced autocrine positive feedback loop by promoting the Orai1/AKT-dependent proliferation via the stimulation of Orai1 expression and function.

SUBMITTER: Radoslavova S

PROVIDER: S-EPMC8156432 | biostudies-literature |

REPOSITORIES: biostudies-literature

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