Pancreatic ductal adenocarcinoma (PDAC) is currently the 4th leading cause of cancer related deaths in the world. One of the principal characteristics of PDAC is the presence of a dense “desmoplastic reaction”, mainly constituted of pancreatic activated stellate cells (PSCs), that often accounts for more than half of the tumor volume. However, the cellular and molecular mechanisms regulating their activation remains little known. Calcium acts as a universal and versatile second messenger in the regulation of cellular processes including cancer. The store operated calcium channels (SOCs) represent one of the major calcium entry pathways in non-excitable cells. Recently, we showed the involvement of ORAI1 and STIM1 in calcium entry (SOCE) and survival in PDAC cell lines (Kondratska et al.2014). Here, we aimed to assess the role of ORAI1 and TRPC1, two of the main SOC actors, in the human activated PSC cell line PS-1. ORAI1 and TRPC1 expression was detected in both mRNA level by qPCR and in protein level by Western Blot, in PS-1 cell line. The silencing of ORAI1 and TRPC1 by siRNA transfection resulted to a significant decrease (siCtrl: 100±1.99%, siORAI1: 66.93±1.45%, siTRPC1: 37.72±5.09%; N=3; P<0.001) of SOCE induced by thapsigargin (measured by calcium imaging). Moreover, ORAI1 and TRPC1 knockdown strongly decreased PS-1 proliferation (siCtrl: 100±5.79%, siORAI1: 36.70±3.78%, siTRPC1: 50.68±5.03%; N=3; P<0.001) without affecting their mortality (evaluated by MTT assays). These results were confirmed by using the pharmacological SOCs inhibitors SKF96365 at 5µM (DMSO: 100±5.01% vs SKF96365: 50.87±2.80%; N=3; P<0.001) and 2APB at 50µM (DMSO: 100±5.89% vs 2APB: 43.23±3.12%; N=3; P<0.001). Furthermore, calcium also regulates the α-SMA expression, the principal marker of stellate cell activation, in hepatic stellate cells (Iyer SC et al.2015). We then investigate the impact of ORAI1 and TRPC1 silencing on α-SMA protein expression in pancreatic stellate cells. We found that silencing of TRPC1 but not of ORAI1 induced 58.36% decrease of α-SMA protein expression (N=4, P<0.01). Interestingly, α-SMA knockdown induced 60.92% decrease of TRPC1 protein expression (N=3, P<0.05) and decrease of PS-1 cell proliferation (siCtrl: 100±6.89% vs si α-SMA: 45.81±4.43%; N=4; P<0.001). In conclusion, we demonstrate that the human activated PSCs are characterized by a SOCE which is ORAI1 and TRPC1 dependent. Both ORAI1 and TRPC1 are required for activated PSC proliferation, probably by maintaining a calcium entry. Moreover, it seems that a feedback regulation exists between TRPC1 and α-SMA expression that regulates cell proliferation. However, more experiments are needed to determine the mechanism by which ORAI1 and TRPC1 regulate PSC proliferation, as well as the link between TRPC1 and α-SMA expression.